In 1956, Newborn began to perform in New York City, recording his first album as a leader in that year, Here Is Phineas for Atlantic Records. His trios and quartets at that time included his brother Calvin on guitar, bassists Oscar Pettiford, George Joyner and drummers Kenny Clarke and Philly Joe Jones. Newborn created enough interest internationally to work as a solo pianist in Stockholm, Sweden, in 1958 and in Rome, Italy, the following year. He drew much critical acclaim, for both his leonine technique and meticulously artful playing at any tempo. The most often-noted feature of Newborn's playing is fast-tempo parallel improvisation, two octaves apart in the manner of Oscar Peterson, which requires great ambidexterity.

On March 16, 1960, 29-year-old Newborn replaced Thelonious Monk and performed "It's All Right with Me" on the ABC-TV series Music for a Spring Night. Newborn moved to Los Angeles that year, and recorded a sequence of piano trio albums for the Contemporary label. Critics often noted his playing style as being too technical, and Newborn developed emotional problems as a result. He was admitted to the Camarillo State Mental Hospital for some periods, and suffered a nervous breakdown related to conflicts with a record label during his career. Newborn later sustained a hand injury that hindered his playing.

Newborn's later work was intermittent due to ongoing health problems. This is most true of the period from the mid-1960s to mid-1970s when he faded from view, underappreciated and underrecorded. He made a partial comeback in the late 1970s and early 1980s, although this return ultimately failed to benefit his financial situation. He died in 1989 after the discovery of a growth on his lungs and was buried in Memphis National Cemetery.

Despite his setbacks, many of Newborn's records, such as Phineas' Rainbow, The Great Jazz Piano of Phineas Newborn Jr., and Harlem Blues, remain highly regarded. Jazz commentator Scott Yanow referred to Newborn as "one of the most technically skilled and brilliant pianists in jazz." Evidence of his technical prowess can be heard on tracks such as "Sometimes I'm Happy", from the album Look Out – Phineas Is Back!, on which Newborn performs extended, complex, and brisk solos with both hands in unison. Leonard Feather said of him, "In his prime, he was one of the three greatest jazz pianists of all time." Oscar Peterson said, "If I had to choose the best all-around pianist of anyone who's followed me chronologically, unequivocally ... I would say Phineas Newborn, Jr."