Hoechlin appeared in commercials as a baby, which he discovered at the age of eight. This led him to successfully audition at an acting school, and obtain an agent. His first role, at the age of 11, was in Happy Haunting, a Disney Sing-Along Songs video. At the age of 13, Hoechlin was selected from 2000 auditionees to play Michael Sullivan, Jr. in Road to Perdition alongside Tom Hanks. Hoechlin was nominated for multiple awards for the role, and won both the Saturn Award for Best Performance by a Younger Actor and the Young Artist Award for Best Performance in a Feature Film – Leading Young Actor. That performance led to him getting the role of Martin Brewer in the television show 7th Heaven in 2003. Initially booked for a two-episode arc, he became a recurring character for the rest of the season. Hoechlin was nominated for a 2004 Teen Choice Award for Breakout Male Star for the role, and remained a regular character for the following four years, amassing further nominations for a Teen Choice Award and a Young Artist Award. The show worked around Hoechlin's baseball schedule, filming on days he did not have practice or a match, throughout high school and his first year of college.

Hoechlin began playing baseball at the age of seven. He played throughout high school, playing in the Area Code Games in both 2004 and 2005. He earned a scholarship to Arizona State University, where he played infield, and the team made it to the College World Series in Omaha, Nebraska. In 2008, after a year at Arizona State, he transferred to the University of California, Irvine. He played infield as a second baseman for the UC Irvine Anteaters. During this time, he also played in collegiate summer leagues.

Hoechlin was born in Corona, California, to Lori and Don Hoechlin. He has two brothers, Tanner and Travis, and an older sister, Carrie. He graduated from Santiago High School in 2006.

After 7th Heaven ended in 2007, he had small roles in other television series, including CSI: Miami and Castle. He also returned to film work. Hoechlin starred in the 2007 David DeCoteau film Grizzly Rage and was in the 2008 movie Solstice. He also appeared alongside Owen Wilson and Christina Applegate in the 2011 movie Hall Pass.

Following his decision to commit to acting full-time and commencing in 2011, Hoechlin played werewolf Derek Hale in the television series Teen Wolf. He was a regular on the show for the first four seasons, and returned as a guest star for the sixth and final season in 2017. During the early seasons of the show, filmed in Atlanta, Georgia, Hoechlin lived with co-stars Tyler Posey and Dylan O'Brien. BuddyTV ranked him #3 on its list of "TV's Sexiest Men of 2011". Throughout Teen Wolf's run, the cast won the Best Ensemble award at the 2013 Young Hollywood Awards and Hoechlin won the 2014 Teen Choice Award for Choice TV Male Scene Stealer.

Hoechlin was cast as Superman on the CW show Supergirl in 2016. Hoechlin was Producer Greg Berlanti's first choice for the role, and did not have to audition. Describing the casting as "surreal", he said he hoped to successfully embody the optimism of the character and maintain the idea of Superman as a symbol of hope. He appeared in four episodes of the show's second season, and was nominated for a Saturn Award for Best Guest Performance on a Television Series for his work in the role. His portrayal of Superman was well-received by fans and critics and described as "fun" and a "breath of fresh air".

Hoechlin has a number of completed films awaiting release. In February 2017, it was announced that he was cast in the upcoming Peter Hutchings teen drama Departures, starring alongside Asa Butterfield, Maisie Williams, and Nina Dobrev. He will appear in The Domestics, a post-apocalytic thriller alongside Kate Bosworth and Lance Reddick. Hoechlin has also completed filming George Gallo's Bigger, in which he stars as Joe Weider. The biopic reunites Hoechlin with Teen Wolf co-star Colton Haynes, and tells the story of the Weider brothers founding the International Federation of Bodybuilders.