Sklenar was born and raised in Northern New Jersey to Bruce Feakins and Francine Sklenar. His mother is of Czechoslovakian descent.
Sklenar made his professional film debut in the 2011 film Cornered. The following year, he appeared in the television series Dating Rules from My Future Self. He then appeared in the film Chance in 2014, the NBC comedy series Truth Be Told in 2015, the films Hunky Dory and Bella Donna, and the television series Fall into Me in 2016, a lead role in the American-Japanese horror film Temple and the Fox sitcom series New Girl in 2017.
He was then cast as Edward Mapplethorpe in the 2018 biographical drama film Mapplethorpe, which follows the life of New York photographer Robert Mapplethorpe. It screened at Tribeca Film Festival in 2018 where it was named a Runner-up in the U.S. Narrative Competition section. Sklenar received positive critical acclaim from multiple media outlets for his performance in Mapplethorpe, including from Boy Culture who praised him for "[having] maximum impact in [his] psychologically charged scenes with [Matt] Smith" He appeared in the 2018 biographical drama film Vice, opposite Amy Adams, Steve Carell, Christian Bale and Sam Rockwell. The film explores the life of politician Dick Cheney and is directed by Academy Award-winner Adam McKay. Sklenar then appeared in Amir Naderi's film Magic Lantern, in addition to films The Last Room and Glass Jaw. In June 2018, Sklenar was also cast in the independent drama film Indigo Valley, which is based on director Jaclyn's Bethany's short film of the same name. That same year, Sklenar was cast as the lead antagonist in The Big Ugly, a noir crime thriller that weaves the British gangster genre with the American western, opposite Ron Perlman, Malcolm McDowell, Nicholas Braun and Leven Rambin. For his work in the film as Junior Lawford, Sklenar received wide critical praise. Richard Roeper of the Chicago Sun Times stated, "Brandon Sklenar gives a screen-popping performance as Junior; he’s fantastic as a monster cloaked in a James Dean persona."

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