Major acts on the label in the 1950s included blues singers Jimmy Reed, Memphis Slim, and John Lee Hooker, and rhythm and blues vocal groups the Spaniels, the Dells, and the El Dorados. The 1960s saw the label become a major soul label with Jerry Butler, Gene Chandler, Dee Clark, and Betty Everett having hit singles on both the pop and R&B charts. Vee-Jay was also the first label to nationally issue a record by the Pips (through a master purchase from the tiny Huntom label of Atlanta), who became Gladys Knight and the Pips in 1962 when they moved to Fury Records.
Vee-Jay had significant success with pop/rock and roll acts, such as the Four Seasons (their first non-black act) and the Beatles. Vee-Jay acquired the rights to some of the early recordings by the Beatles through a licensing deal with EMI, as the American affiliate Capitol Records was initially uninterested in the group. The main attraction at the time, however, was another EMI performer, Frank Ifield. Calvin Carter later said, "There was a number one record over in England at the time—It was 'I Remember You' by Frank Ifield. We took the record, and as a throw in, they had a group and asked us if we would take them, too. The group turned out to be the Beatles and we got a five-year contract on the Beatles as a pickup on the Frank Ifield contract."
In the mid-1960s, Vee-Jay signed the former successful child singer Jimmy Boyd, known for the hit "I Saw Mommy Kissing Santa Claus"; Boyd was then twenty-five years old. The company ventured into folk music with Hoyt Axton and New Wine Singers, and also picked up Little Richard who re-recorded his Specialty hits and recorded (1965) "I Don't Know What You've Got (But It's Got Me)", an R&B success, with Jimi Hendrix, Don Covay, Bernard Purdie, Ronny Miller, and Billy Preston (before he became successful on his own).
Vee-Jay's jazz line accounted for a small portion of the company's releases, but recorded such artists as Wynton Kelly, Lee Morgan, Eddie Harris, and Wayne Shorter. The A&R for the jazz releases was Sid McCoy. The company also had a major gospel line, recording such acts as the Staple Singers, The Famous Boyer Brothers, the Argo Singers, Swan Silvertones, the Caravans, Dorothy Love Coates and the Gospel Harmonettes, and Maceo Woods. Vee-Jay even released comedy on LP, with records by Dick Gregory, and Them Poems, Mason Williams' early nightclub act, recorded with a studio audience in 1964.