Conigliaro was signed by the Red Sox in 1962, at the age of 17. In 1963, he batted .363 with 24 home runs playing for the Wellsville Red Sox in the New York–Penn League, after which he was called up to the majors.

During his 1964 rookie season, Conigliaro batted .290 with 24 home runs and 52 RBI in 111 games, but broke his arm and his toes in August. In his first at-bat in Fenway Park, Conigliaro hit a towering home run in the second inning against the White Sox.

In his sophomore season in 1965, Conigliaro led the league in home runs (32), becoming the youngest home run champion in American League history. He was selected for the All-Star Game in 1967. In that season, at age 22, he not only reached a career total of 100 home runs, but attained that milestone at the youngest age for an American League player.

On August 18, 1967, the Red Sox were playing the California Angels at Fenway Park. Conigliaro, batting against Jack Hamilton, was hit by a pitch on his left cheekbone and was carried off the field on a stretcher. He sustained a linear fracture of the left cheekbone and a dislocated jaw with severe damage to his left retina. The batting helmet he was wearing did not have the protective ear-flap that has since become standard (partly due to this serious incident)

A year and a half later, Conigliaro made a remarkable return, hitting 20 homers with 82 RBI in 141 games, earning Comeback Player of the Year honors. In 1970, he reached career-high numbers in HRs (36) and RBI (116). That season he and his brother Billy formed two-thirds of the Red Sox outfield. After a stint with the Angels in 1971, he returned to the Red Sox briefly in 1975 as a designated hitter, but was forced to retire because his eyesight had been permanently damaged.

In September 1975, after his retirement, Conigliaro was hired by WJAR TV 10 in Providence, Rhode Island as a sports anchor; in August 1976, he moved to a similar position at KGO-TV Channel 7 in San Francisco.

On January 9, 1982, then 37-year-old Conigliaro was in Boston to interview for a broadcasting position when he suffered a heart attack while being driven to the airport by his brother Billy. Shortly thereafter, he suffered a stroke and lapsed into a coma. Conigliaro never fully recovered and suffered slight brain damage due to the stroke, until his death more than eight years later, in February 1990, at the age of 45 from pneumonia and kidney failure. In commemoration, the Red Sox wore black armbands that season. He is buried in Holy Cross Cemetery in Malden, Massachusetts.