Second-half goals from Preston pair Keith Keane and teenager Josh Brownhill ensured Peter Taylor's second spell as Gillingham boss started with a defeat.
Taylor, who led the Kent club into the Championship 13 years ago, was appointed interim-manager on Monday after Martin Allen was sacked.
But it was not the return he had hoped for as the visitors deservedly came away from the Priestfield Stadium with all three points.
Keane opened the scoring from close-range a minute after the restart as his right-footed shot deflected off Gills defender Adam Barrett and past the helpless Stuart Nelson.
Brownhill - making his full debut for the Lillywhites - doubled the visitors' advantage from 12 yards six minutes later following good play from Stuart Beavon.
Chris Whelpdale wasted two brilliant opportunities for the Kent side in between the Preston goals, but turned provider 15 minutes from time when Gills' leading scorer Danny Kedwell headed in a consolation goal from his free-kick.
But any other outcome would have been unfair for the visitors, for whom Beavon, Chris Laird and Kevin Davies had all gone close to opening the scoring in the first half.