Hossa scored his team-high 34th goal on a power play 6:51 into the game, rookie Ville Leino scored an even-strength goal late in the first period and Zetterberg's short-handed goal 4:08 into the second put Detroit ahead 3-0.
Christian Ehrhoff scored on the power play midway through the second period to avoid a shutout, but the Sharks simply couldn't generate enough offensively to make a comeback. They did, however, have one apparent goal negated by video review.
Zetterberg whiffed on an opportunity to give Detroit a two-goal lead in the first period, but he made up for it -- twice.
The San Jose Sharks may have a problem if they meet up with the Red Wings in the playoffs. They cannot play in Joe Louis Arena.
All-Time In Regular Season
*Outscored 10-1 this season at Joe Louis
He blocked a shot in the Detroit zone, raced with the puck up the ice, did a 360-degree spin between the circles and snapped a wrist shot past Nabokov.
"I tried to get back," said Ehrhoff, who helplessly tried to defend the play. "It would've been nice if I stopped as quick as him, but I couldn't."
Late in the third period with a two-man advantage, Zetterberg started to wrap around the net for a shot only to stop, pivot and score on the short side of the net.
"I've seen Hank do that a lot," said San Jose coach Todd McLellan, a former Detroit assistant. "He holds on to the puck a little longer than most."
Jaw-dropping goals don't do much for him.
"It's the win that counts," Zetterberg said.
The Red Wings have won three of their last four games and nine of their last 12.
San Jose had won four straight, following a 1-2-4 stretch that cut into its cushion atop the standings.
While both teams appear to be the class of the conference and perhaps the NHL, the Western Conference's top-seeded teams have met just three times in the conference finals since 1999.
"We can't look that far ahead," Conklin said.
If they do meet again in a few months, the atmosphere will likely be similar to what it was at Joe Louis Arena on Wednesday night.
"That felt like the playoffs, didn't it?" Holland asked.
The storied arena was packed, there were a lot of hits -- some after the whistle -- and a lot of talent on display.
Just 2 minutes into the game, Detroit's Dan Cleary was penalized for boarding Joe Thornton after landing a hit on his back that led to his head slamming against the glass.
"It was just a hit," Thornton said. "It was just a hit -- from behind."
San Jose F Claude Lemieux was booed early and often by fans, who still regard him as a villain for his role in the Avalanche-Red Wings rivalry. "I thought they were cheering," he joked. ... Detroit D Brad Stuart played after missing 14 games with back and rib injuries. ... Leino scored his first NHL goal on Jan. 31 and has five in just 11 games. "It doesn't matter who we play with Leino, he scores," Babcock said. ... San Jose coach Todd McLellan was Detroit's top assistant last season. ... Detroit C Pavel Datsyuk assisted on the final goal, giving him 500 points in his career. "I think he's one of the most gifted players in the game," Babcock said. "But he's underrated." ... Conklin hasn't lost since Nov. 26 at Joe Louis Arena and is 13-1 overall at home.