During Waldron's period as house pianist for Prestige Records in the late 1950s, he appeared on dozens of albums and composed for many of them, including writing his most famous song, "Soul Eyes", for Coltrane.

A breakdown caused by a drug overdose in 1963 left Waldron unable to play or remember any music; he regained his skills gradually, while redeveloping his speed of thought.

As a pianist, Waldron's roots lay chiefly in the hard bop and post-bop genres of the New York club scene of the 1950s, but with time he gravitated more towards free jazz.

[2] He played alto for local bands that performed for "dances, bar mitzvahs, Spanish weddings", frequently taking over the pianist's role when other musicians took their solos.

[4] After two years in the army,[3] he returned as a student to Queens College in New York, where he studied under composer Karol Rathaus[4] and made the final decision to switch from saxophone to piano.

[7] This decision was influenced in part by hearing Charlie Parker's virtuoso speed on saxophone,[5] and by not having the extroverted personality Waldron thought necessary for that instrument.

in music in 1949, Waldron worked for a short time in rhythm and blues bands, including with Big Nick Nicholas.

[7] He was pianist on several Mingus recordings, including Pithecanthropus Erectus, which was a key development in the movement towards freer collective improvisation in jazz.

[7] Waldron formed his own band in 1956, which consisted of Idrees Sulieman (trumpet), Gigi Gryce (alto saxophone), Julian Euell (bass), and Arthur Edgehill (drums).

[11] Waldron was Billie Holiday's regular accompanist from April 1957 until her death in July 1959,[9] including for the all-star television broadcast The Sound of Jazz.

[5][8] Waldron appeared on several McLean-led recordings, and was praised by critic John S. Wilson for these performances as being "a consistently interesting and inventive pianist, who apparently can create fresh and provocative ideas even in the midst of a shrilling bedlam".

Waldron often used his own arrangements and compositions for the Prestige sessions, of which his most famous, "Soul Eyes", written for Coltrane,[13] became a widely recorded jazz standard following its initial appearance on the 1957 album Interplay for 2 Trumpets and 2 Tenors.

[7] Around this time, Waldron's playing on his own recordings became darker, featuring emotional shifts and variations in minor keys.

[10]: 382–3 In addition to writing for his own band and those led by others, Waldron wrote and arranged for early play-along records that were published by Music Minus One.

About a year after the overdose, his physical recovery was sufficient to allow him to start relearning his skills, which he did partly by listening to his own records.

[18] His recovery as a musician continued for another two years, as his speed of thought was still too slow over that period to allow genuine improvisation: "I worked out my solos in advance and played what I had written out, until gradually all my faculties returned".

[5]: 72–73  Waldron's stated reasons for settling in Europe were his disgust with the "fierce, cutthroat competition, just to get a job" and the fact that black musicians were paid less than their white counterparts in the U.S.[19] The 1965 score for Three Rooms in Manhattan was followed by one for the American film Sweet Love, Bitter in 1967.

Two of his final recordings were duets with saxophonists who tended, as he did, to play in melodic and free forms: David Murray and Archie Shepp.

[17] When he first played with Mingus, Waldron was a follower of Horace Silver's style, which used added chords and passing notes,[29] as well as Bud Powell's, which contained many runs.

[13] He used thick chords in the lower bass register; his emphasis on weight, texture and frequent repetition of a single and simple motif as opposed to linear and melodic improvisation gave a heavy and dark color to his sound.

One facet of his playing was, according to The Penguin Guide to Jazz, "likened to American minimalism: a slow accretion of almost subliminal harmonic and rhythmic shifts steadily pile up until the music seems ready to overbalance".

[19] He acknowledged the influences of Holiday (on his conception of space and playing behind the beat), Mingus (for the importance of individuality), and Roach (on the value of time signatures other than the usual 4/4), as well as pianists Duke Ellington, Monk, Powell and Art Tatum.