Dempsey, paired alongside Moussa Dembele in attack, took his tally for the season to five with both goals arriving in the first half of an encounter dominated by Mark Hughes' side.
The USA international's brace saw him take centre stage at Craven Cottage, but left-back Carlos Salcido was another outstanding performer.
Salcido, a £1.6million summer signing from PSV Eindhoven, set up the opener for Dempsey and was a constant menace to Wigan's over-worked defence.
The Mexican has become a key attacking weapon and his reputation at Craven Cottage is growing.
Fulham should have claimed their second Premier League victory of the season by a more convincing scoreline given their ascendancy with Zoltan Gera and Brede Hangeland missing chances.
It was Wigan's first defeat in seven games in all competitions and they appeared lethargic, hardly troubling Mark Schwarzer throughout the 90 minutes.
Athletic made five changes to the side that drew with Bolton, among them the return of Gary Caldwell who was making his first Premier League appearance of the season having undergone double hip surgery over the summer.
The Wigan captain was involved in an early goalmouth scramble that was eventually cleared before Hangeland nodded a Simon Davies free-kick over the crossbar.
The lively Davies, who along with Danny Murphy was restored to the midfield after overcoming injury, squared a quickly-taken free-kick when he should have pulled the trigger himself.
Charles N'Zogbia ended a dynamic run by blazing wide of the left post as Wigan enjoyed a rare attacking moment.
N'Zogbia continued to look Wigan's most penetrating player as he darted into space once again, though on this occasion his shot fell straight into the arms of Schwarzer.
Fulham were still the more likely goal scorers, however, and in the 30th minute they crept into the lead through Dempsey.
Murphy sprayed the ball wide to Salcido who dashed forward before delivering a tremendous cross into the six-yard box.
Dempsey drifted in between Antolin Alcaraz and Caldwell before outjumping the latter and heading into the corner to give goalkeeper Ali Al Habsi little chance.
Fulham almost extended their lead but Gera hit the side netting with a sweetly-struck shot and a heartbeat later the Hungarian shook his head in reaction to missing a sitter.
The dangerous Salcido delivered another superb cross which Dempsey appeared to have converted only for Al Habsi to scoop his effort off the line.
The danger was not over as the ball fell to Gera but he somehow nodded over from point blank range.
Fulham were on the rampage and the second arrived a minute before half-time, Chris Baird supplying a wonderful pass that outwitted Caldwell for Dempsey to thump home.
Dembele was eventually crowded out as he zig-zagged his way into Wigan's area before Salcido found the top netting with a speculative lob.
The home defence was largely confined to a watching brief as Wigan struggled to secure any possession.
Fulham continued to dominate but could not produce the decisive ball, though Jonathan Greening caused a few anxious moments with a crafty pass.
Davies slid a ball across goal that the omnipresent Dempsey just failed to meet before stabbing Gera's cross wide.
Gera and Dembele saw attempts foiled by desperate defending as Fulham pressed for a third they richly deserved.
Davies was replaced by Andy Johnson with 10 minutes to go, but the former England striker had little impact as outgunned Wigan focused on damage limitation.