Lamonica lettered in four sports at Clovis High School, was an All-State Quarterback, and turned down a professional baseball contract with the Chicago Cubs. Clovis High School renamed its football stadium Lamonica Stadium in 1974. Lamonica spent his collegiate career at the University of Notre Dame, and was the team's starting quarterback for three seasons.

After a 20-for-28, 349-yard performance in the 1962 East-West Shrine Game at Kezar Stadium in San Francisco, Lamonica was named the game's Most Valuable Player. He was drafted by the Buffalo Bills in the 24th round of the 1963 AFL draft. He was also drafted by the Green Bay Packers in the 12th round of the 1963 NFL draft. Lamonica played with Buffalo for four seasons, backing up Jack Kemp on a team that won back-to-back AFL championships in 1964 and 1965.

In 1967, Lamonica was traded to the Oakland Raiders with Glenn Bass for Art Powell and Tom Flores. In his first year with the Raiders, he threw for 30 touchdowns and ran for four more. In 1969, he threw for 34 touchdowns and more than 3,300 yards. It was in Oakland that Lamonica's passing acumen earned him the nickname "The Mad Bomber."

With Lamonica, the Raiders won three straight Western Division titles and one American Football League Championship. The Raiders made one World Championship Game appearance with Lamonica as quarterback, losing to the Green Bay Packers, 33-14, in Super Bowl II. Lamonica threw for two touchdowns in the game.

Lamonica was a three-time American Football League All-Star and twice was selected as the American Football League's Most Valuable Player, in 1967 and 1969. Lamonica's last season in the NFL was 1974.

In recent years, he hosted a national fishing show on Fox Sports Net called Outdoors with the Pros.