Bill Walsh drafted Clark as the first pick of the 10th round of the 1979 NFL Draft. Clark tallied 506 catches for 6750 yards and 48 touchdowns, along with 50 rushing yards in his eight NFL seasons with the 49ers. He led the NFL in receptions (60) during the strike-shortened 1982 season, and made the Pro Bowl twice, in 1981 and 1982.
Clark's most memorable touchdown came in the 1981 NFC Playoffs. On January 10, 1982, against the Dallas Cowboys, the 49ers trailed 27–21 in the final minute of play. Clark leaped and caught a 6-yard pass from quarterback Joe Montana in the back of the end zone to give the 49ers a 28–27 victory and advance to Super Bowl XVI. That play, one of the most famous in the history in the NFL, has been immortalized as "The Catch". Clark finished the game with eight receptions for 120 yards and two touchdowns. During the 1981 season, Walsh had Montana and Clark routinely practice the 20-yard end-zone throw after regular practice.
After eight seasons with San Francisco 49ers, Clark retired following the 1987 NFL season. He was a member of two Super Bowl-winning teams. To honor his contribution to 49ers, the club retired his number 87. He has served as a team executive for both the 49ers and the Cleveland Browns as well as starring in the lead role in the 1994 direct-to-video comedy Kindergarten Ninja. Clark has also appeared in the video game, All-Pro Football 2K8. He joined Comcast SportsNet Bay Area in 2011 as an analyst for 49ers Postgame Live. In retirement, Clark expressed remorse about the end of Candlestick Park, saying that “It was a dump [but] it was our dump, so we could talk bad about it, but we didn’t want anybody else to talk bad about it.”