Jody Shelley, Tomas Plihal and Patrick Marleau also scored for San Jose, which jumped to a 2-0 lead with two goals in a span of 1 1/2 minutes in the first period.
David Legwand scored for the Predators, who watched Jason Arnott leave on a stretcher after a scary collision late in the first period.
San Jose's Joe Pavelski and Arnott collided and crashed into the net as they both were charging toward the puck. Arnott was pushed head first into Sharks goaltender Brian Boucher and was carried off after lying motionless on the ice for several minutes. He was taken to the hospital for precautionary reasons.
Setoguchi gave San Jose a 1-0 lead at 14:38 in the first period, beating goaltender Dan Ellis with a wrist shot. He has six goals and eight assists in his last 10 games.
Shelley struck at 16:05. Rob Blake took a slap shot from just inside the blue line that ended up in traffic in front of the net. Shelley was able to tap it past Ellis from close range.
San Jose added two more in the second. Plihal fired a wrister from above the left circle that beat Ellis to his stick side and Marleau added a rebound goal.
Legwand ruined Boucher's shutout bid at the 9:27 in the third period. He skated into the slot on a breakaway and converted the rebound when his first shot bounced off Boucher.
Notes:@ Shelley's goal was his first since March 3 against Montreal. ... The clock stopped with 2.4 seconds left in the first when Arnott was injured. Players cleared the benches for intermission and played the final 2.4 seconds at the end of the break. ... The Predators are 5-2-0 at home this season.