He first performed in a Broadway show in 1998 as the Squeegee Man and Roger understudy in Rent; he also starred as the last Roger in the final Broadway company of Rent, which was recorded for the theatrical release entitled Rent: Filmed Live on Broadway. His additional Broadway credits include Miss Saigon (with the original star Lea Salonga playing Kim to close the Broadway production); The Full Monty, as Jerry Lukowski replacement (2001); Lennon (2005); Aida (Radames replacement, 2003–04), another role originated by Pascal; and Tony in Billy Elliot the Musical. He was also in A Little Princess the Musical as Captain Crewe. In 2005, he played Neville Craven in the 2005 World AIDS Day The Secret Garden concert. In 2006, he starred in the short lived High Fidelity on Broadway, and starred as Valentin in Kiss of the Spider Woman at Signature Theatre in Arlington, VA, for which he received a nomination for the 2009 Helen Hayes Award for Outstanding Lead Actor. He appeared in The Pajama Game opposite Kate Baldwin at The Muny in July 2007. He also starred in Oklahoma in 2007 at the Lyric Theatre opposite Kelli O'Hara, as well as the Broadway musical The Story of My Life, with Malcolm Gets in February 2009. He was nominated for the 2013 Tony Awards for Tony Award for Best Featured Actor in a Musical for his role as John Jasper / Mr. Clive Paget in the revival of The Mystery of Edwin Drood.

Chase's television guest appearances include the recurring role of Pat Mahoney on Rescue Me, Cupid, Canterbury's Law, Law & Order, Third Watch, Conviction, and Queens Supreme. He had a small role in the 2000 film Shaft. Chase guest-starred in the Law & Order: Criminal Intent episode "Passion" in July 2009.

Chase has two daughters with Lori Chase, to whom he was married from 1998 to 2008. He married Stephanie Gibson on November 15, 2009; they split in late 2011 before filing for divorce in January 2012.

His television appearances include Hallmark's The Lost Valentine, alongside Jennifer Love Hewitt and Betty White; the 2011 season finale of Royal Pains (USA); Blue Bloods (CBS); and the ABC drama Pan Am. In 2012, he appeared on the series White Collar, in the episode "Neighborhood Watch", and appeared on the series Unforgettable, in the episode "The Comeback". He also guest starred as Michael Swift in the NBC series Smash. He also played the role of country superstar Luke Wheeler on the television series Nashville.

He plays the title role in the 2013 film Butterflies of Bill Baker. Chase voices Angee in A Warrior's Tail (2016).

Chase assumed the role of william Shakespeare from Christian Borle in the Broadway musical Something Rotten! on July 18, 2016.

He started as Neil Hargrove in the second season of the American supernatural horror-science fiction web television series, Stranger Things, which premiered on Netflix on October 27, 2017.