Upton attended a casting call in Miami for Elite Model Management in 2008 and was signed the same day. She eventually moved to New York City, where she then signed with IMG Models. In April 2011, an Internet video of her doing the dougie hip-hop dance at a Los Angeles Clippers game went viral and served to increase her popularity. Upton made an appearance in a June 2011 episode of Tosh. Celebrity Softball Game at Chase Field in Phoenix, Arizona, in July 2011.
Upton’s acting debut was in the film, Tower Heist, as Mr. It was released in November 2011. She also appeared in The Three Stooges as Sister Bernice. Upton appeared on the cover of the 2012 Sports Illustrated Swimsuit Issue, released in February 2012. Upton has also recounted the negative aftereffects of the 2012 Sports Illustrated cover, as she was subjected to criticism and felt she had been objectified.
She has appeared in advertising campaigns for David Yurman, Sam Edelman, Betsey Johnson, Guess? In 2012, she was ranked the fifth-sexiest model by Models. Hot 100 list, citing her photo shoots with Sports Illustrated. Upton was the cover model for the 2013 Sports Illustrated Swimsuit Issue for the second consecutive year. In September 2013, Upton was named Model of the Year at the 10th annual Style Awards at the Mercedes-Benz Fashion Week in New York. Upton appeared on the flip-side cover of the 2014 50th-anniversary Sports Illustrated Swimsuit Issue, the first time that type of cover was used by that magazine. Part of her shoot took place at Cape Canaveral, capturing her in zero gravity.
In April 2014, she appeared with Cameron Diaz, Leslie Mann, and Nikolaj Coster-Waldau in the comedy The Other Woman as Amber, one of Coster-Waldau’s character’s mistresses. In 2014, Upton starred with Tony Hale in Lady Antebellum’s music video “Bartender”. In 2017, Upton starred with Alexandra Daddario in The Layover, a road trip sex comedy directed by William H. Upton has said that her belief in God is important to her. During a photo shoot, someone joked about a cross necklace she wore, saying, “Why are you wearing a cross? Like you would be religious”, then took the necklace from her to do the shoot. Upton stated about the incident: “I was really affected by that.