After her stint with Krupa, O'Day joined Woody Herman's band. She left the band after a year and returned to Krupa. Singer Jackie Cain remembers the first time she saw O'Day with the Krupa band. "I was really impressed," she recalls. She (O'Day) sang with a jazz feel and that was kind of fresh and new at the time." Later, O'Day joined Stan Kenton's band with whom she cut an album that featured the hit tune "And Her Tears Flowed Like Wine."

In the late '40s, O'Day struck out on her own. She teamed up with drummer John Poole; they played together for the next 32 years. Her album "Anita," which she recorded on producer Norman Granz's new Verve label, elevated her career to new heights. She began performing in festivals and concerts with such illustrious musicians as Louis Armstrong, Dinah Washington, George Shearing and Thelonious Monk. O'Day also appeared in the documentary filmed at the Newport Jazz Festival in 1958 called "Jazz on a Summer's Day" making her an international star.

Throughout the '60s she continued to tour and record while addicted to heroin, and in 1967 she nearly died from an overdose. She eventually beat her addiction and returned to work. In 1981, she published her autobiography "High Times, Hard Times" which, among other things, talked candidly about her drug addiction.