In 2002, Howerton starred as Corey Howard in the ill-fated That ’80s Show. He went on to guest star on ER as Dr. Nick Cooper in 2003. He had small roles in the films Must Love Dogs (2005), Serenity (2005), Two Weeks (2006), and The Strangers (2008). He also appeared as a nurse in Crank (2006), and reprised the role in its 2009 sequel, Crank: High Voltage. Howerton is most notably involved in It’s Always Sunny in Philadelphia (2005-) as one of the main cast, producer and director, and has also written numerous episodes. He planned to be executive producing on the comedy show Boldly Going Nowhere with his It’s Always Sunny in Philadelphia co-creators, before the show was delayed. Howerton had a recurring voice role on The Cleveland Show as Ernie Krinklesac, as well as recurring roles on the Fox comedy series The Mindy Project and the FX dark comedy series Fargo. He starred in the 2013 comedy film Coffee Town. He also had a bit part as the gun running Dominic, in the 2016 Netflix Original Officer Downe, starring Kim Coates. He also starred in the 2018 NBC comedy A.P. Bio.

On September 8, 2009, Howerton married actress Jill Latiano, who guest starred on the It’s Always Sunny in Philadelphia episode “The D.E.N.N.I.S. System” two months later. Their first son, Miles Robert, was born in 2011. The couple had a second son, Isley Ray, in August 2014.