Chenier began his recording career in 1954, when he signed with Elko Records and released Cliston's Blues , a regional success. In 1955 he signed with Specialty Records and garnered his first national hit with his label debut "Ay-Tete Fi" . The national success of the release led to numerous tours with popular rhythm and blues performers such as Ray Charles, Etta James, and Lowell Fulson. He also toured in the early days with Clarence Garlow, billed as the Two Crazy Frenchmen. Chenier was signed with Chess Records in Chicago, followed by the Arhoolie label. In April 1966, Chenier appeared at the Berkeley Blues Festival on the University of California campus and was subsequently described by Ralph J. Gleason, jazz critic of the San Francisco Chronicle, as "... one of the most surprising musicians I have heard in some time, with a marvelously moving style of playing the accordion... blues accordion, that's right, blues accordion." Chenier was the first act to play at Antone's, a blues club on Sixth Street in Austin, Texas. Later in 1976, he reached a national audience when he appeared on the premiere season of the PBS music program Austin City Limits. Three years later in 1979 he returned to the show with his Red Hot Louisiana Band. Chenier's popularity peaked in the 1980s, and he was recognized with a Grammy Award in 1983 for his album I'm Here. It was the first Grammy for his new label Alligator Records. Chenier followed Queen Ida as the second Louisiana Creole to win a Grammy. Chenier is credited with redesigning the wood and crimped tin washboard into the vest frottoir, an instrument that would easily hang from the shoulders. Cleveland Chenier, Clifton's older brother, also played in the Red Hot Louisiana Band. He found popularity for his ability to manipulate the distinctive sound of the frottoir by rubbing several bottle openers along its ridges. During their prime, Chenier and his band traveled throughout the world.
Since 1987, his son C. J. Chenier has carried on the zydeco tradition by touring with Chenier's band and recording albums. In 1989, Chenier was inducted posthumously into the BluesHall of Fame, and in 2011, was inducted into The Louisiana Music Hall of Fame. Rory Gallagher wrote a song in tribute to Chenier entitled "The King of Zydeco". Paul Simon mentioned Chenier in his song "That Was Your Mother", from his 1986 album Graceland, calling him the "King of the Bayou." Sonny Landreth recalls growing up on the rhythm of Clifton and Cleveland and the Red Hot Louisiana Band in South of I-10, songtitle and name of the album released in 1995. John Mellencamp refers to "Clifton" in his song "Lafayette", about the Louisiana city where Chenier often performed. The song is on Mellencamp's 2003 album Trouble No More. Zachary Richard mentioned Chenier in his song "Clif's Zydeco". The Squeezebox Stompers' "Zydeco Train" says, "Clifton Chenier, he's the engineer." The jam band Phish often covers Chenier's song "My Soul" in live performances. Chenier is the subject of Les Blank's 1973 documentary film, Hot Pepper. In 2015, the Library of Congress deemed Chenier's album Bogalusa Boogie to be "culturally, historically, or artistically significant" and selected it for preservation in the National Recording Registry.