In 1961, Palmieri founded the band Conjunto La Perfecta, which featured singer Ismael Quintana. Apart from the big bands, at the beginning of the decade the Charanga was the Latin dance craze. Essential to the Charanga style is the five key wooden flute and at least two violins. Palmieri decided to replace the violins with two trombones for a heavier sound.
Two key elements to the 'Palmieri' sound were trombonists Barry Rogers (who was very influential to the fourth chords sound that Palmieri is known for) and Brazilian-born Jose Rodriguez. Together they were responsible for many of the 'head' arrangements, mambos and monas that the band recorded. George Castro(flute), Manny Oquendo(bongo), Tommy Lopez(conga) and Andy Gonzalez/Dave Perez (bass) rounded out the group. To this day, the group is known as one of the swingingest, danceable, innovative and influential groups of that period.
Palmieri experimented by including a touch of jazz in his recordings, and incorporating a popular Cuban rhythm known as mozambique. Lo Que Traigo Es Sabroso (What I Bring is Saucy) andMozambique are just two examples of his use of this rhythm. Seeking a bigger and punchier sound, Palmieri disbanded the band in 1968.
In 1971, Palmieri recorded Vamonos Pa'l Monte (Let's go to the Hills) with his brother Charlie at the organ. That same year he also recorded Eddie Palmieri & Friends in Concert, At the University of Puerto Rico. In 1974, Palmieri became the first Latin musician to win a Grammy Award for Best Latin Recording with The Sun of Latin Music (produced by Harvey Averne and (arranged by Rene Hernandez and Barry Rogers (Un Dia Bonito)). On July 21, 1979, he appeared at the Amandla Festival along with Bob Marley, Dick Gregory and Patti LaBelle, among others.
In the 1980s, Ismael Quintana returned to the band, which also included Cheo Feliciano. Palmieri won two Grammys for the recordings of Palo Pa Rumba and Solito. He also recorded the albumLa Verdad (The Truth) with salsa singer Tony Vega in 1987. Next year the happiness of his success was set back by the sudden death of his brother, Charlie.
In the 1990s, Palmieri had participated in various concerts and recordings with the Fania All-Stars and the Tico All-Stars; he also introduced La India with the production of Llegó La India via Eddie Palmieri (La India has arrived via Eddie Palmieri), released in 1992. In 2000, Palmieri announced his retirement from the world of music. However, he recorded Masterpiece with Tito Puente and won two Grammys; additionally he was also named the "Outstanding Producer of the Year" by the National Foundation of Popular Culture. Palmieri has won a total of 9 Grammy Awards in his career, most recently for his 2006 album Simpático. On November 6, 2004, Palmieri directed a "Big Band Tribute" to his late brother Charlie at Avery Hall at the Lincoln Center for the Performing Arts.