Werkheiser was born in Atlanta, Georgia, and raised in Johns Creek, Georgia. His parents enrolled him in acting classes at the Talent Factory, a local children’s acting program.
After landing a minor role in We Were Soldiers, Werkheiser and his mother moved to Los Angeles to pursue his acting career. In 2003, he had a main role as Max Korda in the TV movie Recipe for Disaster. Since his arrival in Hollywood, Werkheiser has landed several television and film roles, the biggest of which is that of Ned Bigby on Ned's Declassified School Survival Guide. Werkheiser lent his voice in movies such as: Casper's Scare School the voice of as Casper the Friendly Ghost, Casper's Shadow, and Good Dragon and The Wizzard of Krudd as the voice of Gordo.
In 2007, Werkheiser starred in Nickelodeon movie based on Wendelin Van Draanen's Shredderman book series Shredderman Rules as Nolan Byrd/Shredderman. Later that year, Werkheiser played the role of Chris Marino in Lifetime original movie Christmas in Paradise. In 2009, Werkheiser starred as Victor in the movie The First Time. He played the role of Victor, who has an incurable crush on hot senior Anya who is way out of his league and she doesn't have clue he exists. He also had a significant role in the movie The Prankster, in which he played the role of Brad Burris.
In 2011, Werkheiser played the role of Danny in the horror thriller movie Beneath the Darkness. In 2012, he played the lead role of Cassidy Warren in web series Never Fade Away. In 2013 Werkheiser starred as Max in the horror film The Wicked. He played the supporting role of Brett in Lifetime movie Zephyr Springs also known as Deadly Spa. In 2014, Werkheiser starred as Nick Behrle in the movie California Scheming and had a role as Fitch in the movie Helicopter Mom. In 2015, he starred as Andy in the short film Arthur.
In 2016, Werkheiser starred as Jason in the television movie Bad Sister, which premiered on Lifetime on January 4, 2016; in the movie his character is stalked by the school's newest nun. He is hosting DanceOn's first competition series Dance-Off Juniors on free mobile-streaming service Go90 which will be judged by Alyson Stoner, Matt Steffanina, Ladia Yates, and Todrick Hall and will premiere on April 20, 2016.
In summer 2016, Werkheiser starred as Logan in the romantic comedy film Sundown directed by Fernando Librrija and co-starring Camilla Belle, Sean Marquette, and Sara Paxton. The movie is about a couple of BFFs (Devon Werkheiser and Sean Marquette) who travel to Puerto Vallarta hoping to hook up with their high school crushes.
On December 5, 2016, he guest starred in an episode of 2 Broke Girls. He has finished filming Veracruz and Where's the Money.
Werkheiser originally signed with Universal Motown for his debut studio album, however his label status on MySpace has since changed to unsigned, possibly indicating that he is no longer with Universal. His album, which has been described as being a combination of rock and pop, will feature him singing and playing the guitar. Werkheiser has requested that he be able to co-write the lyrics and music of all of his songs, and he has been working with artists including Tim Myers, Wally Gagel, Eddie Galan, and Charlie Midnight to help write his songs. He performed live shows with female vocalists Kristen Marie Hollyin and Britney Christian and plans to go on live tours after the release of the album.
His first single, a full band production of "If Eyes Could Speak", was released April 1, 2010 on iTunes. The official music video was released via YouTube on June 15, 2010. It stars himself and his partner, Molly McCook. His second single, "Sparks Will Fly", was released July 29, 2010 on iTunes.
He planned to release an extended play, which would in turn lead to an eventual release of an album. Werkheiser had written over 45 songs, though he hadn't decided which to include on an EP or album.
He released his first EP named I Am on June 25, 2013. On June 9, 2015, he released his second EP named Here and Now. On January 3, 2016, Werkheiser released a single "Stuck On the Ground". He released another single "Fire" on January 22, 2016. On January 29, 2016, Werkheiser released a stripped version of his single "Stuck on the Ground".