Born in Pittsburgh, Pennsylvania, he is of Polish and Italian ancestry. He attended St. Regis Catholic Elementary School before going to Central Catholic High School in Pittsburgh, where he also started in baseball, and won Parade All-American honors in football. As a high school ball player, Marino hit high school highs by throwing up to 95 mph. He was drafted by the Kansas City Royals baseball team in the 1979 amateur draft, but decided to play college football instead.

Marino played college football at the University of Pittsburgh from the 1979 to the 1982 season. As a freshman in 1979, Marino led the Panthers in a 24-17 triumph over West Virginia in the Backyard Brawl with 252 yards and a field goal. Marino threw for 256 yards and also rushed for 40 yards. He led the Panthers to a last-minute triumph over the Georgia Bulldogs in the 1982 Sugar Bowl by throwing the game-winning pass to tight end John Brown with less than a minute remaining, a play that is considered among the greatest in Pittsburgh sports history. The next season (his senior year) was considered a disappointment with regard to the preseason Heisman Trophy and national championship hype. His team lost the 1983 Cotton Bowl 7-3 to Southern Methodist and their "Pony Express" of Eric Dickerson and Craig James. Although he lost the Heisman Race, Marino's Panthers triumphed once again over rival West Virginia with a late touchdown drive to win 16-13 in one of the best games in the rivalry.