In 2006, 17-year-old O'Pry was scouted from his prom photos on MySpace by John Yannella Studio Fifty Nine

Since then, O'Pry has been featured in numerous advertising campaigns and editorials for Calvin Klein, Giorgio Armani, Versace, Dolce & Gabbana, Ralph Lauren, Gianfranco Ferré, H&M, Massimo Dutti, Zara (retailer), Armani Jeans, Marc Jacobs, Emporio Armani, Lacoste, DSquared², American Eagle, Bottega Veneta, DKNY, Fendi, GQ, Dazed & Confused, V, Details, Barneys, Uniqlo, Bloomingdale's, Belstaff, D2, Arena, Diesel, Gap, JOOP! and Numéro Homme.

His runway credentials include opening Versace, Yves Saint Laurent, Givenchy and Salvatore Ferragamo, closing Moschino, Trussardi and Zegna, and both for Balmain. Other designers he has walked for include Roberto Cavalli, Louis Vuitton, Chanel, Michael Kors, and Hermès. In November 2011, O'Pry was selected as the star of Viktor & Rolf's Spicebomb fragrance campaign.

O'Pry appeared in Madonna's music video "Girl Gone Wild". He also appeared in Taylor Swift's music video for her song "Blank Space", as her love interest.

In 2008, O'Pry was named the world's eighth most successful male model by Forbes magazine. Only one year later, he had moved up to the #1 position on their list. As of September 2013, Models.com named O'Pry as the most successful male model in the world on their 'Top 50' list. As of 2014, he had held that position for two years.

In 2015, O'Pry was included on Models.com's new 'Supers Men', 'Sexiest Men', and the 'Money Guys' lists. That same year, Vogue, ranked him fifth on the 'Top 10 Male Models of All Time'.