Detroit trailed 3-0 at the start of the third period but quickly erased that deficit and set the stage for Zetterberg's winner. Nicklas Lidstrom gloved down a deflected puck on a rush and passed it to Zetterberg, who had the entire left side of the net behind Rick DiPietro to fire his wrist shot into.
Tomas Holmstrom, Niklas Kronwall and Dan Cleary also scored for Detroit, which got 16 saves from Dominik Hasek.
Mike Sillinger, Shawn Bates and Jason Blake had goals for the Islanders, who have points in four straight games (2-0-2).
Just as they salvaged a point with a spirited comeback in an overtime loss at Atlanta last Friday, the Islanders gave one away on home ice.