Palmieri first played timbales in his uncle's orchestra before switching to piano. His older brother Charlie (1927-1987) was already a pianist; as a teenager Eddie would accompany his brother to the Palladium to see Charlie play in Tito Puente's group, which lasted from 1922 until Puente's death in 2000.

In the 50s, Palmieri played in the orchestra of Cuban balladeer Vicentico Valdés (to this day, when Palmieri's orchestra plays a bolero, it is second to none) and the legendary Puerto Rican singer Tito Rodríguez. He debuted his group, La Perfecta, in 1962. A milestone in New York Latin music, the group featured singer Ismael Quintana and timbalero Manny Oquendo, and brought a hard-hitting trombone sound to New York dance music with a 2-bone section of Barry Rogers and the Brasilian José Rodrigues. After the group disbanded in 1968, Palmieri continued recording as a solo bandleader.

An intellectually rigorous composer, Palmieri's work aggressively delves into the meaning of African culture in the Spanish-speaking world. His playing and arranging carries more of the harmonic innovations of twentieth-century European music--clusters, whole-tone scales, fearless dissonance, systematized composition--than any other salsa pianist's. Never overly prolific, Palmieri is a notorious perfectionist in the studio; all his records are good. One album in particular deserves special mention: his 2000 collaboration with Tito Puente for what would be Puente's final album: Masterpiece.