The Miami Dolphins selected Mandich in the second round (twenty-ninth overall pick) of the 1970 NFL Draft, and he played for the Dolphins from 1970 to 1977. He played in all fourteen regular season games in 1970, and had one three-yard reception for a touchdown against the Houston Oilers on September 27. During the Dolphins unbeaten 1972 season Mandich had a touchdown reception against the Minnesota Vikings and two (in two games) against the New England Patriots. In the playoffs he had two catches, a five-yarder against the Pittsburgh Steelers and a 19-yarder in Super Bowl VII. His most productive year was 1974, as he had 33 receptions for 374 yards and six touchdowns. He did not play in Miami's losing playoff game with the Oakland Raiders. Mandich's final touchdowns came in 1976 against the Patriots, the Jets twice, and Baltimore Colts. In 1978 he went to the Steelers but had no receptions in ten games.
Mandich was the radio sports talk show host on WIOD 610 AM from 1983 to 1987, and joined WQAM 560 in 1987. He also did color commentary on Dolphins radio broadcasts on which he was teamed with Jimmy Cefalo and Joe Rose. He was known for his trademark soundbite "All right, Miami!" When he gave out the call-in number for cell phone users, he playfully told his radio listeners to call "if you're riding around with the windows down." Diagnosed with cholangiocarcinoma, a cancer of the bile duct, in early 2010, Mandich became absent from his afternoon show. In the fall of 2010, the terminally ill commentator returned to the broadcast booth for his final season of game-day color commentary.
Mandich was a partner in the Hialeah, Florida construction sub-contractor firm of LotSpeich and Co. He also was a partner in a bar called Ziggy's in the Florida Keys.
On December 4, 2011, during halftime of the Oakland Raiders vs. Miami Dolphins game, Mandich was posthumously inducted into the Miami Dolphin Honor Roll—a ring around the second tier at Sun Life Stadium that honors former players, coaches, contributors, and officials who have made significant contributions to the Miami Dolphins franchise.