Williams grew up Catholic[2] in a French Creole-speaking home in St. Martinville, Louisiana, the youngest of seven children.

[3] He developed his musical sensibility in his hometown, a place rich in folk tradition, following in the footsteps of his uncle, the Creole guitarist Harry Hypolite, who was a band member with both Clifton Chenier and later with his son C. J.

[3] Sid opened a club in Lafayette, El-Sid-O's, and Nathan became a regular Friday night performer there.

After their successful performances as well as those by John Delafose and Beau Jocques, the venue began to host zydeco bands every Thursday night beginning in spring 1993.

[12] Early in his career, The New York Times wrote that the then-25 year old Williams was "poised to become important; already he is being mentioned as one of the people revitalizing the genre".

[15] For more than three decades, Nathan & the Zydeco Cha Chas have toured widely, performing at venues as diverse as his brother's convenience store in Lafayette, Louisiana to the Lincoln Center in New York and the Grand Ole Opry in Nashville, Tennessee.

Non-family band members have included bassists Paul Newman and Wayne Burns, drummers Herman "Rat" Brown and Gerard St. Julien Jr., Clifford Alexander on rubboard, and Allen "Cat Roy" Broussard on saxophones.

[3][5][9] On his 1995 album Creole Crossroads, Williams teamed up with Cajun fiddler Michael Doucet from the band BeauSoleil.

[22] Nathan & the Zydeco Cha-Chas were nominated for a 2023 Grammy Award in the Best Regional Roots Music Album category, for Lucky Man.

Since then, he has led his own band, Lil' Nathan and the Zydeco Big Timers, playing accordion and keyboards.

[27] His older brother Dennis Paul Williams, in addition to being a jazz and zydeco guitarist, is a well-known visual artist, whose mixed media works have been exhibited in multiple U.S. cities and in Europe.