With the loss, Anaheim fell to 7-18-3 on the season and 5-7-0 on home ice.
Trevor Zegras scored Anaheim's only goal, his 10th of the season. Cam Fowler and Dmitry Kulikov added assists.
John Gibson made 15 saves in two periods of action before Anthony Stolarz replaced him in net for the third. Stolarz, who made his sixth relief appearance of the season, stopped 7-of-8 shots he faced.
Timo Meier, Scott Harrington, Erik Karlsson, Nico Sturm, Nick Bonino and Steven Lorentz scored for the Sharks, who earned their third road win of the campaign (3-8-5) and improved to 9-16-5 overall. Tomas Hertl, Matthew Benning and Alexander Barabonov tallied two assists.
Makiniemi earned his first career NHL win in his first start, stopping 23-of-24 Anaheim shots.
Meier put the visitors ahead first midway through the opening period, finishing off an absurd pass by Karlsson along the right wing wall. The veteran defenseman evaded the Ducks defense along the boards, getting to the hashmarks before delivering a textbook backdoor pass right on Meier's tape for the tap-in goal.
The 26-year-old Meier has goals in four of his last five games against Anaheim.
Despite the 1-0 score, the game was a back-and-forth battle for nearly all of its first 27 minutes until it suddenly wasn't, breaking wide open on three San Jose goals in a span of 104 seconds.
The first and third of those goals came on some tough luck for Anaheim, with a couple crazy bounces finding their way to the back of the net.
Harrington, a 29-year-old former second round pick known more for his defensive prowess, doubled the Sharks' advantage on a shot from the point. Winger Kevin Labanc set Harrington up for a one-timer near the top of the zone, which the defenseman hammered off the stick of Cam Fowler, shattering it in two, before carroming through traffic in front of Gibson and past the netminder for Harrington's first goal of the season.
With the goal, the seventh of Harrington's 214-game NHL career, the Ontario native now has points in two of his four appearances this season.
The Sharks lead hit three two shifts later when Karlsson beat Gibson with a slapshot from distance, using a Ducks defender attempting to block the shot as a screen and lifting his bid over Gibson's blocker after a low-to-high pass by Alexander Barabonov behind the net.
Karlsson has points in four straight games (1-4=5) and leads NHL defensemen with 37 (12-25=37) on the season. He has seven points in three games against Anaheim this season.
Sturm capped the scoring barrage on a ridiculous bounce, finding himself in the right place at the right time for one of the easiest goals of his hockey career. Winning the faceoff immediately following Karlsson's goal, the Sharks dumped the puck into the offensive zone, with Gibson going back to get it for Anaheim. But as the puck hit the zamboni door in the corner, it bounced right out in the slot, where Sturm swiped it home to give the Sharks a 4-0 lead.
A member of Colorado's Stanley Cup championship team last season, Sturm has 7-2=9 points in his first 22 games with San Jose.
Anaheim got on the board shortly after, getting back within three when Zegras took a stretch pass from Fowler and beat Makiniemi with a wrister from the top of the circles.
