Hornsby was born in Newport News, Virginia, on December 1, 1975. He is a cousin of musician Bruce Hornsby. He grew up in Houston, Texas, and majored in acting at Carnegie Mellon University.
Hornsby plays defrocked priest Matthew "Rickety Cricket" Mara on the FX comedy series It's Always Sunny in Philadelphia, also serving as an executive producer and writer on the show. He appeared as Steve "The Hutch" Hutchinson on The Joe Schmo Show, and as Patrick on Six Feet Under. His first animated role was Fanboy in Fanboy & Chum Chum. He also starred in the independent film Pretty Bird.
Hornsby appeared in Pearl Harbor, Minority Report, and Flags of Our Fathers (in which he played USMC photographer Louis R. Lowery). He created and performed in the podcast Yoda and Me along with Loren Tarquinio. He adapted and created the CBS sitcom How to Be a Gentleman, serving as its lead actor, writer, and producer; CBS canceled the series in its first season. Hornsby co-wrote, designed characters, and lent his voice to FX's cartoon Unsupervised, which lasted for one season. Most recently, he created the NBC pilot for Mission Control, produced by Gary Sanchez Productions for NBC a workplace sitcom set at NASA's Johnson Space Center circa 1965.

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