In 2012, she was ranked the fifth-sexiest model by Models.com She ranked #3 on the American publication of AskMen's Top 99 Women for 2013. In 2012, she was listed on Maxim's 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. Parts of her 2013 Sports Illustrated pictorial were filmed in Antarctica and Upton suffered from failing hearing and eyesight due to the extreme cold.
After getting the November 2012 Vogue Italia cover photographed by Steven Meisel and the January 2013 Vogue UK cover, Upton landed the June 2013 Vogue cover by Mario Testino. She was then photographed by Annie Leibovitz for the October 2013 100th anniversary cover of Vanity Fair.
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". People named Upton its "Sexiest Woman" for 2014, the first time the title has been awarded. Also in 2014, Upton was the centerpiece of a $40 million advertising campaign for Machine Zone's mobile app Game of War: Fire Age.
In 2017, Upton starred with Alexandra Daddario[ in The Layover, a road trip sex comedy directed by William H. Macy. The film follows two best friends (Daddario and Upton) on vacation as they fight over the same man during a layover in St. Louis. Also that year, Upton appeared in James Franco's film adaptation The Disaster Artist, about the production of the film The Room.