After completing a short film, Fernandez made his debut television appearance in a 2006 episode of Cold Case, followed by minor roles in Drake & Josh and Lincoln Heights. His screen debut came two years later, in 2007, when he landed the role of Edgar in Interstate before returning to TV. He landed his first recurring role in Jericho as Sean Henthorn between 2006 and 2007. The series was cancelled after just one season before a campaign by fans saw it return for a second before being cancelled once again.

In 2008, Fernandez became one of the front-runners to play Edward Cullen after he auditioned for Catherine Hardwicke in her Venice Beach garage, during the casting of Twilight. Fernandez was allegedly Hardwicke's first choice, but it was up to Kristen Stewart who had the last say. Shiloh later recalled on his narrowly missed opportunity, "At the time, it was just another audition. I didn't realize I was missing out on stardom and giant paychecks. Now, looking back on it, I certainly wouldn't have been mentally stable enough to deal with all that. Lucky for me, not getting that part led to other work that was a much better fit for me." Fernandez, who had no formal training, admitted being bashful around other actors during rehearsals. Having done an array of television shows (CSI:NY, The United States of Tara) including starring in the Gossip Girl episode "Valley Girls" as Owen Campos, alongside Brittany Snow and Krysten Ritter. He eventually landed his first big break playing a troubled small-town Texas rink manager in the 2010 Sundance hit Skateland with Twilight alum Ashley Greene.

Though he lost the Twilight role to Robert Pattinson, Hardwicke liked Fernandez enough to cast him in what would be his first romantic lead, in Red Riding Hood, opposite Amanda Seyfried. The role became his Hollywood movie breakthrough, making him a hot commodity. MTV Networks' NextMovie.com named him one of the 'Breakout Stars to Watch for in 2011'. As he shot into the spotlight, he was the cover model of Nylon Guys' March 2011 issue, introducing him as "Hollywood's New Rebel", and was the cover man for the April/May 2011 issue of Da Man magazine.

In 2013, Fernandez starred in the remake of Evil Dead and in the independent film Syrup, based on the novel of the same name by Max Barry. In March 2015 Fernandez, earned one of the leading roles in the Canadian thriller film Backcountry, who will star along Rossif Sutherland, Joel Kinnaman, Tom Holland, Percy Hynes-White and Rachelle Lefevre.

Fernandez has spoken about smoking pot during his high school days to help him relax, and has stated that he does not "need to be stoned anymore. Weed was never fun for me—I was just uncomfortable with myself so I wanted to be stoned. But just being comfortable in my own skin now means I don't have to do it". His favorite movie of all time is The Thing Called Love and River Phoenix is his idol. Fernandez has stated that if he were not acting, he would have majored in Spanish, moved to South America, and run a Banana farm or worked in construction, because he is good with his hands; or, if he was better at it, a Writer. Fernandez has an affinity for country music, and his dream role is to play a country music star. He is a friend of actor Thomas Dekker.