James Raymond Simpson was born in Hackettstown, New Jersey, on November 21, 1975. He has two older brothers. He attended Hackettstown High School, where he took his first acting class. After graduating from Bloomsburg University with a BA in theater, he acted for four seasons at the Williamstown Theatre Festival in Williamstown, Massachusetts.

In 2000, Simpson made his feature film debut in the teen comedy Loser. This was followed by various roles on television, including the Stephen King miniseries Rose Red and appearances on 24, NYPD Blue, Cold Case, and Carnivàle. Subsequent film roles included Herbie: Fully Loaded (2005), Seraphim Falls (2006), and Zodiac (2007). In 2008, Simpson starred as Philo T. Farnsworth in The Farnsworth Invention on Broadway. His portrayal was described as “superb” by The Chicago Tribune, and earned him a Theatre World Award. From 2008 to 2009, Simpson made several guest appearances as an intern named Lyle on The Late Show with David Letterman. During that time, he also appeared in episodes of CSI: Crime Scene Investigation, My Name is Earl, House, and Psych, as well as having supporting roles in the films The Invention of Lying (2009), and Date Night (2010). Other notable credits include the cult comedy series It’s Always Sunny in Philadelphia, on which he has appeared as Liam McPoyle over several seasons, and the A&E series Breakout Kings, where he starred as Lloyd Lowery.

Simpson met actress Melanie Lynskey in 2001, while working on Rose Red. They married in April 2007. Lynskey filed for divorce in September 2012, citing irreconcilable differences, and they were divorced in May 2014.

From 2012–2014, Simpson appeared in the films Abraham Lincoln: Vampire Hunter, The Truth About Emanuel, and White House Down. He then appeared as Gavin Orsay, a recurring character, on the Netflix series House of Cards (2014–2015). For this, Simpson—along with the rest of the main cast—was nominated on two occasions for the Screen Actors Guild Award for Outstanding Performance by an Ensemble in a Drama Series. In 2016, Simpson starred in the first season of SundanceTV’s series Hap and Leonard. That same year, he appeared in a principal role on the first season of HBO’s series Westworld. His portrayal of William, a visitor to the titular futuristic Wild West-themed amusement park populated by androids, was described as “spellbinding” by Variety. For his work on Westworld, he was once again nominated for the Screen Actors Guild Award for Outstanding Performance by an Ensemble in a Drama Series. For his performance in the second season, he received a Primetime Emmy Award nomination for Outstanding Guest Actor in a Drama Series.

In 2017, Simpson starred in “USS Callister”, the first episode of the fourth season of the anthology sci-fi drama series Black Mirror. For his performance, he received a nomination for the British Academy Television Award for Best Supporting Actor.

Simpson married actress Sophia Del Pizzo in April 2019.