Upton attended a casting call in Miami for Elite Model Management in 200 and was signed by them the same day. She eventually moved to New York City, where she then signed with IMG Models.
Upton first modeled for Damien Haumpy Garage, then Dooney & Bourke. She was the 2010–2011 face of Guess. In 2011, Upton appeared in the Sports Illustrated Swimsuit Issue. She was featured in the body paint section and named Rookie of the Year for the issue. She has since modeled for Beach Bunny Swimwear, and has appeared in Complex and Esquire as "The Woman of the Summer".
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. On April 30, 2012, a bikini-clad Upton performing the "Cat Daddy" by The Rej3ctz in a video directed by Terry Richardson also went viral, amassing almost 750,000 views in the first 24 hours.
Upton made an appearance in a June 2011 episode of Tosh.0, filmed in Fort Cobb, Oklahoma, participating in a segment called "Knife or Banana", emulating a Japanese game show in which she is stabbed with a banana.
Upton played in the 2011 Taco Bell All-Star Legends & Celebrity Softball Game at Chase Field in Phoenix, Arizona, in July 2011.
Upton's acting debut was in the film, Tower Heist, as Mr. Hightower’s Mistress. She followed up with an appearance in The Three Stooges as Sister Bernice.
Upton appeared on the cover of the 2012 Sports Illustrated Swimsuit Issue, unveiled on February 13, 2012, on the Late Show with David Letterman.
Upton, who was previously considered a swimsuit model, has recently made her way into high-fashion magazines with editorials in American Vogue and Italian Vogue, both photographed by Steven Meisel. Kate has been featured on the covers of Vogue Italia, British Vogue, CR Fashion Book, Cosmopolitan, French ELLE, GQ, Italian GQ, German GQ, Jalouse, Sunday Times Style, Esquire, The Daily, and Muse Magazine. She has appeared in fashion editorials for American Vogue, Vogue Spain, V Magazine, Harper’s Bazaar, and Russian Interview, and has worked with photographers such as Steven Meisel, Terry Richardson, Alasdair McLellan, Bruce Weber, Sebastian Kim, Guy Aroch, Matt Jones, Miguel Reveriego, Norman Jean Roy, Josh Olins, Gilles Bensimon, Yu Tsai, Sebastian Faena, Walter Iooss, Ellen von Unwerth, and Stewart Shining. A favorite of high-fashion notables such as Stephen Gan, Tonne Goodman, Carlyne Cerf, Carine Roitfeld, and Katie Grand, Kate was also shot for the Metropolitan Museum of Art’s “Schiaparelli and Prada: Impossible Conversations” Exhibition Catalogue in 2012. Models.com exclaims, “The sexy market just got a little more competitive thanks to the meteoric rise of Kate Upton. The Sports Illustrated swimsuit edition was a major coup, but the momentum keeps building with cover after cover. We can’t remember the last time a newbie made such a splash!”
In 2012, she was ranked the 5th sexiest model on MODELS.com's Top Sexiest Models
She ranked #3 on the American publication of AskMen's Top 99 Women for 2013, behind only Jennifer Lawrence (#1) and Mila Kunis (#2).
In 2012, she was listed on Maxim's HOT 100 list, citing her photo shoots with Sports Illustrated.
On February 8, 2013, it was announced that Upton would be the cover model for the 2013 Sports Illustrated Swimsuit Issue, making her the first model to appear on the cover of consecutive annual Swimsuit issues since Tyra Banks in 1996 and 1997. Parts of her 2013 Sports Illustrated pictorial were filmed in Antarctica, which was the first fashion shoot on that continent. Filmed during the Antarctic summer, temperatures on location are reported to have been around 32 °F with windchill bringing it to about 0 °F. Because of the cold she could not film for more than a minute at a time before being warmed again. By the end Upton suffered from failing hearing and eyesight, symptoms that are commonly associated with frostbite but can also be signs of hypothermia.
As of April 2013, she is ranked the #3 sexiest model just behind Adriana Lima and Gisele Bundchen on MODELS.com's Top Sexiest Models.