After winning the 2012 Miss Rhode Island USA competition on the first pageant she entered, she went on to win the Miss USA pageant on June 3, 2012.

On July 6, 2012, the city of Cranston, Rhode Island held a homecoming celebration for Culpo for her pageant win. At an outdoor ceremony held at Cranston City Hall, Mayor Allan Fung presented Culpo with the key to the city.

Culpo represented the United States at the Miss Universe pageant that was held on December 19, 2012, in Las Vegas, Nevada. She won the competition, becoming the eighth representative from the United States to win the title and the first since 1997. Culpo has also become the first Rhode Islander to win the title. She succeeded outgoing titleholder Leila Lopes from Angola.

In January 2013, Culpo visited Indonesia for three weeks and helped crown the winner of Puteri Indonesia 2013 on February 1 in Jakarta. She also visited Yogyakarta, Surabaya, and Bali during her visit. In Jakarta, Culpo hosted a discussion with young Indonesians for the United Nations Population Fund on HIV and youth prevention at the United States Embassy’s cultural center of America.

On August 25, 2013, Cranston’s city council approved a resolution adding Culpo’s name to Albert Avenue, which runs the length between Broad Street and Narragansett Boulevard in Edgewood.

On September 10, 2013, Culpo walked in the Sherri Hill fashion show held at the Trump Tower in New York City. Culpo was in India from September 27 until October 6. On November 9, 2013, she crowned Gabriela Isler of Venezuela as her successor.

From 2013 to 2015, Culpo dated musician Nick Jonas. She was romantically linked to athlete Tim Tebow until November 2015. Culpo was in an on-again-off-again relationship with football player Danny Amendola from February 2016 to April 2019. During the summer of 2019, she started dating another football player Christian McCaffrey.

In August 2017, Culpo opened a restaurant with her family in Rhode Island.

Culpo became a social media personality after gaining a significant following on Twitter, Instagram and YouTube, and has partnered and collaborated with several beauty and fashion brands like L’Oréal, Kipling, and Uberliss as an influencer. Culpo has also featured in the Sports Illustrated Swimsuit Issue, and appeared on the cover of the 2020 issue alongside Jasmine Sanders and Kate Bock. She also appeared in the reality television show Model Squad (2018). In addition, Culpo had roles in the films I Feel Pretty and Reprisal in 2018.