Raised in Austin, Texas, Charliemade his debut with Pictures For Pleasure in 1985 at age 16. He followed that up with a self-titled second album when he was 20. Because word of his reputation as a prodigy guitar player spread far and wide, he found himself an in-demand session player while still in his late teens, and he had the opportunity to record with Ron Wood, Keith Richards and Bob Dylan.

Born to a mother who was just 16 when she gave birth to Charlie, he and his mother moved to Austin when he was just four. His mother would get him out to clubs like the Armadillo World Headquarters and the Soap Creek Saloon. Places like the Split Rail and Antone's blues club became his classrooms.

After living outside of Austin for a while with his mother, Charlie moved back to Austin when he was 12, and the musicians around Austin, his heroes, people like Jimmie Vaughan and Stevie Ray Vaughan, Joe Ely and others, took him in and helped him develop his talents as a musician. By the early 1980s, while Charlie and his brother Will Sexton were still young boys, they were both taught how to play guitar by the local Austin legend W. C. Clark, known as the "Godfather of Austin Blues".

While still in his late teens, Sexton's skills as a guitar player were in great demand, and he became a popular session player, recording with artists such as Ronnie Wood, Keith Richards, Don Henley, Jimmy Barnes and Bob Dylan. He eventually followed up his debut with the self-titled album Charlie Sexton, recorded at the age of twenty.

In 1999, Charlie was hired by Bob Dylan to replace Bucky Baxter. Sexton had previously played with Dylan during a pair of Austin, Texas concerts in 1996, and on some demos recorded in the fall of 1983. Charlie’s residency with Dylan from 1999-2002 brought him great exposure, with many critics singling out the interplay between him and Larry Campbell, who was also a guitarist in Dylan's backing band. Hailed as one of Dylan's best bands, the group recorded a number of studio recordings, including Things Have Changed (from the 2000 film Wonder Boys) and 2001's critically acclaimed album, Love and Theft. He also performed and appeared with them in 2003's Masked & Anonymous.

In late 2009, Charlie rejoined Dylan's tour band replacing Texan friend, Denny Freeman, for some dates in October going into November.

As a songwriter, Charlie writes about what he knows and Texas themes permeate his songs. He considers Bob Dylan his strongest songwriting influence, while he counts Austin legends Jimmie Vaughan and the late Stevie Ray Vaughan among his prime influences for guitar playing.