Born on December 15, 1940 in Springfield, Massachusetts, Buoniconti graduated from Notre Dame, and was drafted by the Patriots in the thirteenth round of the 1962 AFL draft. He made an immediate impact with the Patriots for, helping the team capture the 1963 AFL Eastern Division title. With Boston, he appeared in five AFL All-Star Games, and recorded 24 interceptions, which is still the seventh-most in team history. He was traded to the Miami Dolphins in 1969.

He continued to play well with the Dolphins, in 1969-1974 and 1976, and made the AFL All-Star team in 1969 and the NFL Pro Bowl in 1972 and 1973. His leadership made him a cornerstone of the team's defense. During his years there, the team advance to three consecutive Super Bowl appearaces, one of which was the team's 1972 undefeated season. In 1973, he recorded a then-team record 162 tackles (91 unassisted). He was named to the Pro Bowl in 1972 and 1973.

Buoniconti got his law degree during his years with the Patriots, and although he was never a practicing attorney, he was briefly President of the US Tobacco Company during the late 1970s and early 1980s. He was a leading critic of studies which showed that smokeless tobacco caused cancer of the mouth as well as other types of cancer.

In recent years, he has become the most outspoken member of the 1972 Undefeated Season team. It is rumored that he leads a champagne toast every year after the last remaining undefeated team loses for the first time.

Nick put his verbal talent to use as a co-host of the HBO series Inside the NFL until 2001. That same year, Nick was named to the Pro Football Hall of Fame.

In 1985, after his son Marc had suffered a paralyzing spinal cord injury in a college football game, he became the public face of the group that founded the Miami Project to Cure Paralysis, now one of the world's leading neurological research centers.