Nathaniel Adams Coles was born on March 17, 1919, in Montgomery, Alabama, and moved with his family to Chicago when he was four. His father, Edward, became a Baptist minister there, and his mother, Perlina, the church organist, taught him to play. He began formal piano lessons at 12, working through jazz, gospel and classical repertoire, attended Wendell Phillips Academy High School, and took part in Walter Dyett's music program at DuSable High School. As a teenager he sneaked out to listen from outside the clubs where Louis Armstrong, Earl Hines and Jimmie Noone were playing, and the Encyclopedia of Alabama adds that he heard Art Tatum and Teddy Wilson at nearby clubs.

At 15 he left school for music. With his older brother Eddie, a bassist, he formed a sextet that made two Decca singles in 1936 as Eddie Cole's Swingsters, and he went on tour with a revival of the musical Shuffle Along, where he met the dancer Nadine Robinson, whom he married in 1937. When the show ended in Los Angeles, the couple stayed. Cole led a big band and played piano in nightclubs until a club owner asked him to form a small group. He hired the bassist Wesley Prince and the guitarist Oscar Moore, and the King Cole Swingsters became the King Cole Trio: piano, guitar and bass, with no drummer. The trio made radio transcriptions and records for small labels, and in 1939 it appeared in New York on a bill with Billie Holiday. Its first hit, "Sweet Lorraine" (1940), led audiences to ask for more vocals, and in 1942 the group became the house band at the 331 Club in Los Angeles. That year Cole also recorded a trio session with Lester Young and the bassist Red Callender. After Prince was drafted in August 1942, Johnny Miller became the regular bassist.

The trio signed with Capitol Records, the label Johnny Mercer helped found in 1942, and its first Capitol session, on November 30, 1943, in Hollywood with Mercer producing, yielded "Straighten Up and Fly Right." Cole wrote it with Irving Mills from a folk tale his father had used in a sermon, and it reached number nine on the pop chart and number one on the Harlem Hit Parade for ten non-consecutive weeks. The trio became Capitol's top-selling group of the 1940s and its only Black act. Cole was also the house pianist for Norman Granz's first Jazz at the Philharmonic concert, at the Philharmonic Auditorium in Los Angeles on July 2, 1944; because of his Capitol exclusivity he was billed on the Mercury releases as "Shorty Nadine" and under other pseudonyms, always as an instrumentalist and never as a singer. He also recorded with Illinois Jacquet and with Young, including a 1946 trio date with the drummer Buddy Rich. In 1946 the trio began the radio series King Cole Trio Time, said to be the first radio program hosted by a Black musician, and its hits included "(I Love You) For Sentimental Reasons" (1946), "The Christmas Song" (written by Mel Tormé and Bob Wells; Cole's first recording is dated June 1946) and "Nature Boy" (1948). Moore left in October 1947 to join Johnny Moore's Three Blazers, and Irving Ashby took over the guitar chair.

From 1950 Cole was billed as a solo singer, usually with strings or a studio orchestra. "Mona Lisa" was the top song of 1950, with an arrangement by Nelson Riddle that was credited to Les Baxter, and "Too Young" was the top song of 1951. In 1950 he also recorded "Orange Colored Sky" with the Stan Kenton orchestra. Riddle arranged many of his 1950s albums, beginning with Nat King Cole Sings for Two in Love (1953), and Gordon Jenkins arranged Love Is the Thing (1957), the only Cole album to reach number one. Jazz critics accused him of selling out, but he kept returning to the piano: in 1956 he made The Piano Style of Nat King Cole, with Riddle conducting and his last instrumental album, and After Midnight, a small-group jazz date with the guitarist John Collins, the bassist Charlie Harris, the drummer Lee Young and guests including the saxophonist Willie Smith, the trumpeter Harry Edison, the trombonist Juan Tizol and the violinist Stuff Smith.

On April 10, 1956, he was attacked on stage in Birmingham, Alabama, by members of the North Alabama Citizens Council, and several of the men were later convicted. From November 5, 1956, to December 17, 1957, he hosted The Nat King Cole Show on NBC, the first nationally broadcast television show hosted by a Black American; it never found a national sponsor, and Ella Fitzgerald, Tony Bennett, Eartha Kitt, Peggy Lee and Mel Tormé were among those who appeared to help it. In 1958 he played W. C. Handy in the film St. Louis Blues and recorded Cole Español in Havana, the first of three Spanish-language albums. He took part in planning the 1963 March on Washington. The 1960s brought hits such as "Let There Be Love" with George Shearing (1961), "Ramblin' Rose" (1962) and "Those Lazy-Hazy-Crazy Days of Summer" (1963).

In December 1964, while working in San Francisco, he was found to have lung cancer, and he made his final recordings there on December 1 to 3 with an orchestra conducted by Ralph Carmichael; they were released as L-O-V-E. His left lung was removed on January 25, 1965, and he passed away at Saint John's Health Center in Santa Monica on February 15, 1965, at age 45. Count Basie and Frank Sinatra were among the honorary pallbearers at his funeral. He received a Grammy Lifetime Achievement Award in 1990 and was inducted into the DownBeat Jazz Hall of Fame in 1997. His daughter Natalie Cole, a singer, joined his 1951 recording of "Unforgettable" on a 1991 duet, and Mosaic's 1991 box set gathered 349 of the Capitol trio recordings.

Cole's place in jazz rests on his piano playing and on the trio he led from 1937 into the early 1950s. The pop-vocal side of his career, orchestral ballads sung in an unhurried baritone from 1950 on, accounts for most of his chart success and for what most listeners know him for, so he is best understood as a jazz pianist whose singing eventually eclipsed his playing. Wikipedia calls his trio the model for the small jazz groups that followed, and the profiles of other musicians on JazzProfiles.com bear that out: Oscar Peterson named Cole among his early models and built his piano-guitar-bass trio on the same format, Herb Ellis modeled the Soft Winds on the Cole Trio, and Ray Charles began with a close copy of his trio sound and voice. The pianists Horace Silver, Tommy Flanagan, Cedar Walton and Hampton Hawes have all named him among the pianists they absorbed, and Art Tatum said in a 1944 interview that he admired Cole's guitarist Oscar Moore. AllMusic's review of The Piano Style of Nat King Cole praised his nimble keyboard work with the Riddle orchestra, and The Penguin Guide to Jazz lists After Midnight in its core collection. Among the singers who followed him is Gregory Porter, who learned phrasing from his mother's Cole records and devoted the 2017 album Nat King Cole & Me to him. Wikipedia adds that many of Cole's later albums, scored for big band without strings but built around the vocal, stayed jazz-based even as he moved away from the trio.