On April 4, 1961, he was part of a five-player trade that sent him to the AFL Boston Patriots, and he went on to become one of the AFL's most productive and colorful players. Playing for the Patriots from 1961 through 1966, Parilli finished his career with over 25,000 total yards and 200 touchdowns, ending among the top five quarterbacks in 23 categories such as passing yards, passing touchdowns and rushing yards. Parilli was selected for three All-Star Games. In 1964, throwing primarily to Gino Cappelletti, Parilli amassed nearly 3,500 yards passing with 31 touchdowns; the latter number was a Patriots record until 2007, when it was broken by Tom Brady. During that season's October 16 contest against the Oakland Raiders, he threw for 422 yards and four touchdown passes in a 43-43 tie. Parilli is a member of the Patriots All-1960s (AFL) Team.
Parilli completed his career with the New York Jets, where he earned a ring as Joe Namath's backup in Super Bowl III, when the Jets stunned the Baltimore Colts by a 16-7 score. Coincidentally, this gave the Jets two quarterbacks from Beaver County, Pennsylvania, with Parilli being from Rochester and Namath being from nearby Beaver Falls and both played for "Bear" Bryant in college. In 1967 it was discovered by Life Magazine that Parilli and several other professional athletes were regular patrons of Patriarca crime family mobster Arthur Ventola's major fencing operation called Arthur's Farm in Revere, Massachusetts. Despite the organized crime connection, journalist Howie Carr stated that there was never any inside information passed between Parilli and Ventola. Arthur was the uncle of mob associate Richard Castucci.
Besides his considerable skills as a quarterback, he was one of the best holders in the history of football and was nicknamed "gold-finger" as a result of kicker Jim Turner's then-record 145 points kicked in 1968 (plus another 19 points in the play-offs and in Super Bowl III). He is one of only twenty players who were in the American Football League for its entire ten-year existence, and is a member of the University of Kentucky Athletic Hall of Fame. In 1982 Parilli was named to the College Football Hall of Fame.
The wide receiver-quarterback duo of Cappelletti and Parilli was nicknamed "Grand Opera".