The loss snapped the Coyotes' seven-game winning streak while the Red Wings picked up their second straight victory on the final leg of their current road trip. The hat trick was the second in Homstrom's nine-year NHL career. Centre Pavel Datsyuk scored the other two goals.
Yanic Perreault scored the lone goal for the Coyotes.
Detroit took a 1-0 lead in the first period with Holmstrom scoring on a power play. It was his 10th of the season and fifth with a man-advantage.
Earlier in the period, an apparent goal from the Red Wings' Kris Draper was disallowed. After a television review, referee Gord Dywer ruled Draper redirected the puck with his skate just outside the crease.
After a scoreless second period, the Coyotes tied it on Perreault's goal 28 seconds into the period.
The Red Wings then answered with four straight goals.
First Holmstrom guided the puck past the goalie at 6:57. Datsyuk then beat Mikeal Tellqvist to make it 3-1. Holmstrom and Datsyuk each scored again for the final margin.
Notes: It was Holmstrom's first two-goal game of the season. ... With their game in Phoenix, the Red Wings concluded a five-game road trip, their longest of the season. ... The Red Wings converted three of their five power play chances.