B. B. King arrived in Memphis for the first time in 1946 to work as a musician, but after a few months of hardship he left, going back to Mississippi. There he decided to prepare himself better for the next visit and returned to Memphis two years later. Initially he worked at the local R&B radio channel WDIA as a singer. In 1949, he began recording songs under contract with Los Angeles-based RPM Records. Many of King's early recordings were produced by Sam Phillips, who later founded Sun Records. King was also a disc jockey in Memphis, where he gained the nickname "Beale Street Blues Boy", later shortened to "B. B." Before his RPM contract, B. B. had debuted on Bullet Records by issuing the single "Miss Martha King" (1949), which got a bad review in Billboard magazine and did not chart well. King is often labelled as "The King of Blues".

In the 1950s, B. B. King became one of the most important names in R&B music, amassing an impressive list of hits including "You Know I Love You," "Woke Up This Morning," "Please Love Me," "When My Heart Beats like a Hammer," "Whole Lotta Love," "You Upset Me Baby," "Every Day I Have the Blues," "Sneakin' Around," "Ten Long Years," "Bad Luck," "Sweet Little Angel," "On My Word of Honor," and "Please Accept My Love." In 1962,B.B. King signed to ABC-Paramount Records, which was later absorbed into MCA Records, and then his current label, Geffen Records.

King's first success outside the blues market was his 1969 remake of Roy Hawkins' tune "The Thrill Is Gone." King's version became a hit on both pop and R&B charts, which was rare for an R&B artist. It also gained the number 183 spot in Rolling Stone's Top 500 Songs Of All Time. He gained further rock visibility as an opening act on The Rolling Stones much-ballyhooed 1969 American Tour. King's mainstream success continued throughout the 1970s with songs like "To Know You Is to Love You" and "I Like to Live the Love."

The 1980s, 1990s and 2000s saw King recording less and less. Yet throughout this time he maintained a highly visible and active career, appearing on numerous television shows and performing 300 nights a year. In 1988 King reached a new generation of fans with the single “When Love Comes To Town”, a collaborative effort between King and the Irish band U2 (on their Rattle and Hum album). In 2000, King teamed up with guitarist Eric Clapton to record Riding With the King. In 1998 B. B. King appeared in "The Blues Brothers 2000" playing the part of the lead singer of the Louisiana Gator Boys, along with Eric Clapton, Dr. John, Koko Taylor, and Bo Diddley.

In 2003, King shared the stage with the rock band Phish in New Jersey, performing three of his classics and jamming with the band for over 45 minutes.

In June 2006, King was present at a memorialization of his first radio broadcast at the Three Deuces Building in Greenwood, Mississippi, where an official marker of the Mississippi Blues Trail was erected.

B. B. King also made an appearance at the Crossroads Guitar Festival put on by Eric Clapton. On the DVD, he plays "Paying The Cost To Be The Boss" and "Rock Me Baby" with Robert Cray, Jimmie Vaughan, and Hubert Sumlin.

In June 2006, a groundbreaking was held for a new B. B. King Museum and Delta Interpretive Center in Indianola, Mississippi. The museum is scheduled to open September 13, 2008.

In June 2008, B. B. King was inducted into the Hollywood Bowl Hall of Fame alongside Liza Minnelli and Sir James Galway.