In this season, Betty decides to move on from Henry and Gio, and after a cross-country trip around the United States, decides to move out of Casa Suarez and into an apartment of her own, hoping that this will help her advance in her quest to move up in the publishing business. Betty also attracts the interest of a musician named Jesse who is living in the apartment across from hers. In addition, she buries the hatchet with Kimberly "Kimmie" Keegan, her childhood nemesis and manager of Flushing Burger, where Ignacio works. Unfortunately, the truce between Betty and Kimmie would be broken after Betty helped Kimmie land a job at MODE and Kimmie reverted to her old patronizing ways after being promoted to associate editor. This promotion would also infuriate Amanda and Marc after Kimmie befriended and then turned on them. But it would be Wilhelmina who would fire Kimmie after she insulted her during a photo shoot with model Adriana Lima.
After his ouster from MODE, Daniel was demoted to Editor-in-Chief of Player magazine, after Alexis decided to bring back Wilhelmina as Editor-in-Chief. Daniel then takes the decision to fight for custody of his son Daniel Jr., and for his Job at Mode, which he takes back from Wilhelmina, whose sudden rise to the top and her means that she lures Betty into her world - by offering her the job of her assistant - in her attempt to mold her. Of course, this doesn't last and when Betty helps Daniel get his job back, she becomes his assistant again. Adding to Wilhelmina's downfall was Marc, whose jealousy over being passed over by Wilhelmina after she lured Betty back to Mode, became a move that prompted Marc to set the downfall in motion for his boss, allowing him to get his job back. In addition, Claire stepped in to stop Wilhelmina from using the family and also to get Hot Flash ready.
Hilda continued to see Tony, who was still married, and when Ignacio found out, it caused a rift between the two. Unfortunately, thanks to his wife, Hilda breaks it off after she talks to her after the woman mistook her for the "other woman [Betty]." Meanwhile, Justin is getting ready to break into show business in Broadway, in what is said to be a "musical episode".
Christina is dealing with Stuart's drug problems and her pregnancy with the unborn Meade baby, which in turn would take a turn for the worse after she is pushed down a flight of stairs. Daniel is framed for it and Betty decides to prove he is wrong. After using some help from Marc and Amanda, they find out Daniel's sister did it. Alexis turns herself in afterwards. While in jail, Alexis reveals to Daniel that a paternity test for Daniel Jr. revealed that Daniel is not the father. Alexis is the father, since she slept with DJ's mother back when she was a man. As a result of the revelation, Daniel Jr's grandparents get custody of the boy.
In the meantime, Wilhelmina puts pressure on Alexis to give up her entire control of the Meade company, in exchange for Wilhelmina's help in getting Alexis' charges dropped. In the end, a compromise is reached, and control of the company is divided equally between Wilhelmina (in actuality, the baby get the share) and Daniel. The two become co-owners and co-editors of the publishing empire. This means Wilhelmina only has 50% to go until she controls the whole empire by herself. The baby, William Slater-Meade, would be born during "Fashion Week 2009" in the middle of the catwalk. The question of William's birthright also became a issue, after Christina started to bond with the boy. Unfortunately, William Slater-Meade in fact turned out to be Christina and Stuart's son, and after some convincing from Betty, Wilhelmina hands the boy over to the McKinneys, who then told Betty that they were moving back to Scotland to start a new life and for Christina, a new fashion business.
Amanda continues the quest to find her father and also moves in with Betty when her spending spirals out of control and her credit card bills became too much for her. Her financial problems would result in Amanda taking on a second job at a pizza parlor in a effort to pay off her debts. Together they plan a "Mode Afterparty." Betty invites Jesse and his band to perform, and he agrees. At the party, he has a sudden case of stage-fright, which Betty helps him get over. However after Betty caught Jesse kissing Amanda and later found him to be boring, Betty gave up on him. She also moved out of the apartment and sublet it to Marc.
As Betty returned home, she found herself and her family deal with Ignacio's heart attack and a new love interest (and his nurse) Elena; Hilda falling for New York City Councilman Archie Rodriguez, who wanted Hilda to apply for a license to operate her beauty shop and Justin's befriending—and rejection—of a bully named Randy. Ignacio would later get a new job at restaurant owned by TV chef Frankie Burrata, whom Ignacio would challenge on his cooking show "Kitchen Rumble."
In the meantime, Wilhelmina falls in love with the new associate and Daniel's business partner Connor Owens, who turned out to be a embezzler after Betty discovered that he was transferring money from the company to him. Surprisingly enough, Daniel would fall for Connor's fiancee Molly, a schoolteacher who later revealed to Daniel that she has cancer. Daniel and Molly would later marry before Molly's death.
Marc is invited to move in with Cliff, but he doesn't know and rejects it. This would cause Marc to fret over this, and in the process would lead to a one-night stand with a guy he met at Betty's rooftop party. Marc then shocked Cliff with a wedding proposal afterwards, but would later confess to Cliff about what he did and the two broke up.
Betty and Marc also become students, participating in the Young Editors Training Initiative (YETI) program. While there, the two must deal with Jodi Papadakis (Bernadette Peters), their professor who wants results from her students. However, it also turned out that Jodi had the hots for gay guys (she tried to flirt with Marc) and cost Betty her shot at landing a editor's job ... by taking it herself. Upon graduating, she and Marc fought over the chance to replace the late Penny Meadows as features editor at MODE. Thanks to a coin toss by Daniel and Wilhelmina, Betty wins the job, leaving Marc devastated.
But that was nothing compared to Betty meeting a rival from Elle, Terri O'Shausseney (Nikki Blonsky), who succeeded by stealing a cover story idea from MODE. Then Betty fell for aspiring sports reporter Matt Hartley, whom Betty later found out that he came from a wealthy family. Matt by the way tried to resist Betty because he had a sexual addiction and was seeing a psychiatrist for treatment, then used his influence to bail out Betty's family. The two would later start dating but the friction would flare up again when Henry returned. Matt thought Betty was over Henry, but after he saw the two kissing (for the last time before Henry left for good), Matt told Betty it was over between them, and on top of that, told her that he will now be her new boss.
Speaking of the Hartleys, Matt's mother Victoria doesn't like Betty and would love to see them apart, while her estranged husband Calvin jumped in to rescue Meade Publications but bought along a secret past involving his affair with Claire (whom Victoria also has a dislike for) that produced a offspring that was supposed to have been aborted, only to be revealed that Claire actually put their son up for adoption.
Finally, the truth of "Fashion Buzz" presenter Suzuki St. Pierre would be discovered by Betty and Daniel after went to New Jersey and discovered that Suzuki (who viewers thought to be gay) was actually Byron Wu, a straight guy who was also married with two sons. It turned out that Byron used the Suzuki alter ego because he could not find work as a serious journalist. Both Betty and Daniel agreed not to expose him.
As the series continues, we see Betty and Matt’s relationship grow as Betty meets his mother who is not too fond of Betty. We later learn that Matt has had impulsive sexual issues and had slept with several women over the years to counteract his loneliness. It isn’t until Betty that he finds someone he truly loves for the first time. Meanwhile, things at Mode are not going well. Conner stole the company’s money and ran. Daniel decides to avoid layoffs and cut backs by liquidating his assets as does Wilhelmina eventually. The company, however, continues to slide downhill and eventually people get fired (like Amanda). It isn’t until Betty and Daniel see inspiration in the form of Matt’s father, Cal Hartley who is interested in helping struggling publications.
While things are starting to look up for Mode, Wilhelmina soon becomes invested in discovering the true identity of her baby, William. She is concerned that the baby was actually Christina’s hence the lack of resemblance with Wilhelmina. Wilhelmina quickly learns that the child is not hers but to keep her stake at the Meade empire, she fakes a DNA test. Christina is shocked and does not believe Wilhelmina. She ends up stealing baby William. Eventually, Wilhelmina admits the child is not her own but only did it to show Cal the power she has and therefore was not fired from Meade once Cal signs the contracts. As a result however, Christina and Stuart along with their child decide to return to Scotland to have the child closer to family (Note: this was done due to Ashley Jensen’s desire to leave the show due to the move to New York and the complications that arose from that for her). Things are better at Meade as Daniel decides to make Molly’s dreams come true by marrying her. Also, Ignacio decides to take his relationship with Elena to the next level. However, once a job opportunity arises for her, Ignacio decides to let her go to follow her own dreams.
At Yeti, Betty and Marc have their final interviews and wait for job call backs. Marc is offered a job at Vouge. As Betty gets an offer to the New York Review, Henry creeps back into her life as well as an offer from Matt to move in together. Betty, unable to hide her past with Henry, is seen kissing him off goodbye by Matt. Betty’s New York Review job ends up being taken by Jodie in a surprising twist. Claire is promoted to Senior Vice President to Wilhelmina’s hatred. Wilhelmina decides she needs dirt on Claire. Wilhelmina learns that Victoria Hartley despises Claire and seeks information. Willie learns that Claire had an affair with Victoria’s ex-husband Cal where Claire became pregnant! When confronted with the accusation, Claire tells Wilhelmina that she decided to abort the child but had to take a year off to deal with the emotional trauma. Wilhelmina asks Claire to resign her position as Senior VP in exchange for keeping her secret.
In the finale episode, we see a struggling and sick Molly fighting for her life as Daniel is nominated for a Mama Award for the Wedding Issue. As a features editor at Mode dies, Betty and Marc vie for the new job and ask Daniel and Wilhelmina to ultimately decide who gets the position. Meanwhile, Matt confronts Betty about kissing Henry and their relationship takes a halt.
The final few moments of the finale involve Mode winning the Mama award for the Wedding Issue where Daniel makes a speech and sees Molly standing behind Betty. He tells her he loves her. Once off the stage, Betty congratulates Daniel but says she did not see Molly at all. We also see that Betty is eventually hired as the features editor over Marc. This was decided over a coin-toss since Daniel and Wilhelmina both decided they were equally qualified. As Betty is getting her new office ready, Matt enters and the couple splits up. Matt reveals that he will be Betty’s new boss since his father offered him a new position at Mode.
Wilhelmina’s position at Meade is being threatened when Cal and Claire both agree that their past is none of Wilhelmina’s business. We see Wilhelmina taking to a privately hired hitman whom she asks to find Connor in order to get the money back and push Cal out with that money. As Wilhelmina leaves the meeting with the hitman, she enters her room at her house, drops her glass and exclaims “What are you doing here?” to an unknown character.
We also see Claire burning an adoption notice meaning Claire in fact did have the child and lied to Wilhelmina about the abortion. Daniel returns home only to find Molly dead and being carried out into an ambulance. Heart-broken and upset, he calls his friend, Betty, for support. The show ends with the two hugging over Molly’s death.