In 1941 Miller was hired to play the King Biscuit Time show, advertising the King Biscuit brand of baking flour on radio station KFFA in Helena, Arkansas, with Lockwood. The program’s sponsor, Max Moore, began billing Miller as Sonny Boy Williamson, apparently in an attempt to capitalize on the fame of the well-known Chicago-based harmonica player and singer Sonny Boy Williamson (birth name John Lee Curtis Williamson, died 1948). Although John Lee Williamson was a major blues star who had already released dozens of successful and widely influential records under the name “Sonny Boy Williamson” from 1937 onward, Miller would later claim to have been the first to use the name. Some blues scholars believe that Miller’s assertion he was born in 1899 was a ruse to convince audiences he was old enough to have used the name before John Lee Williamson, who was born in 1914.

The recordings made by John Lee Williamson between 1937 and his death in 1948 and those made between 1951 and 1964 by “Rice” Miller were all originally issued under the name Sonny Boy Williamson. It is believed that Miller adopted the name to suggest to audiences (and to his first record label) that he was the “original” Sonny Boy. To differentiate between the two musicians, scholars and biographers have referred to John Lee Williamson (1914–1948) as “Sonny Boy Williamson I” or “the original Sonny Boy” and to Miller (circa 1912–1965) as “Sonny Boy Williamson II”.

In 1949, Williamson relocated to West Memphis, Arkansas, and lived with his sister and her husband, Howlin’ Wolf. (Later, for Checker Records, he did a parody of Howlin’ Wolf, entitled “Like Wolf”.) He started his own KWEM radio show from 1948 to 1950, selling the elixir Hadacol. He brought his King Biscuit musician friends to West Memphis—Elmore James, Houston Stackhouse, Arthur “Big Boy” Crudup, Robert Nighthawk and others—to perform on KWEM radio. Williamson married Howlin’ Wolf’s half-sister Mae and he showed Wolf how to play harmonica.

Williamson’s first recording session took place in 1951 for Lillian McMurry of Trumpet Records, based in Jackson, Mississippi. It was three years since the death of John Lee Williamson, which for the first time allowed some legitimacy to Miller’s carefully worded claim to being “the one and only Sonny Boy Williamson”. When Trumpet went bankrupt in 1955, Williamson’s recording contract was yielded to its creditors, who sold it to Chess Records in Chicago. He had begun developing a following in Chicago beginning in 1953, when he appeared there as a member of Elmore James’s band. During his Chess years he enjoyed his greatest success and acclaim, recording about 70 songs for the Chess subsidiary Checker Records from 1955 to 1964. His first LP record was a compilation of previously released singles. Titled Down and Out Blues, Checker released the collection in 1959. A single, “Boppin’ with Sonny” backed with “No Nights by Myself”, was released by Ace Records in 1955.

Sonny Boy took a liking to the European fans, and while there had a custom-made, two-tone suit tailored personally for him, along with a bowler hat, matching umbrella, and an attaché case for his harmonicas. He appears credited as “Big Skol” on Roland Kirk’s live album Kirk in Copenhagen (1963). One of his final recordings from England, in 1964, featured him singing “I’m Trying to Make London My Home”, with Hubert Sumlin providing the guitar.

Upon his return to the U.S., he resumed playing the King Biscuit Time show on KFFA, and performed in the Helena, Arkansas area. As fellow musicians Houston Stackhouse and Peck Curtis waited at the KFFA studios for Williamson on May 25, 1965, the 12:15 broadcast time was approaching and Williamson was nowhere in sight. Peck left the radio station to locate Williamson, and discovered his body in bed at the rooming house where he had been staying, dead of an apparent heart attack suffered in his sleep the night before. Williamson is buried on New Africa Road, just outside Tutwiler, Mississippi at the site of the former Whitman Chapel cemetery. Trumpet Records owner McMurry provided the headstone with an incorrect date of death.

In 1972, Chess released This Is My Story, a compilation album featuring Williamson’s recordings for the label. It was later included in Robert Christgau’s “basic record library” of 1950s and 1960s recordings, published in Christgau’s Record Guide: Rock Albums of the Seventies (1981).

In 2014, Williamson was honored with a marker on the Mississippi Blues Trail in Helena, Arkansas.

On June 25, 2019, The New York Times Magazine listed Sonny Boy Williamson II among hundreds of artists whose material was reportedly destroyed in the 2008 Universal fire.