Senderos nodded home his first ever Cottagers goal in the 89th minute to ensure the hosts followed up their win at the DW Stadium earlier in the season with another deserved victory.
Fulham dominated play by the Thames but the match looked set to end level after Pavel Pogrebnyak had a legitimate goal ignored in an incident which will renew calls for goal-line technology.
Shortly after the Russia international had brought the Whites level following Emmerson Boyce's strike, he saw a 63rd-minute effort hit the underside of the crossbar and, he thought, bounce down over the line.
The 28-year-old wheeled off in celebration, but the officials waved play on having ruled the ball was not fully over.
Pogrebnyak hit the post as Fulham continued to press but, with a draw looking on the card, Senderos nodded home John Arne Riise's free-kick.
Wigan had been on the back foot from the first whistle and were fortunate not to give away a penalty inside a minute when Clint Dempsey burst down the left flank and went down under pressure from Gary Caldwell, with referee Lee Mason waved away the hosts' penalty appeals.
The Cottagers had the Latics penned back in their own half, and only a late challenge prevented a Pogrebnyak cut-back being met from close range by Dempsey.
Jordi Gomez fired over on a rare Wigan attack, before Damien Duff miscued with the goal gaping after a neat free-kick by Danny Murphy.
Wigan began to settle after a slow opening and Victor Moses forced Mark Schwarzer into action with a stinging effort in the 12th minute.
The match became far more even as the first half progressed, with both sides enjoying spells in the ascendancy.
Fulham followed Wigan's spell of dominance with Pogrebnyak and Senderos efforts, before Mousa Dembele saw a fierce drive blocked.
The Whites again came close moments later when neat interplay between Riise and Dempsey allowed the latter to fire the ball across the face of goal.
Nobody could connect with the squared ball but Wigan's foothold on the game was clearly slipping.
Their afternoon got worse in the 33rd minute when striker Franco Di Santo limped off injured and was replaced by Conor Sammon.
Duff curled wide moments after the substitution and Dempsey forced a low save from Ali Al-Habsi as Fulham looked for the opener.
The away support continued to sing "I'm a believer" despite Fulham's dominance and they almost had something else to cheer about with the last chance of the opening 45 minutes, with Gomez forcing Schwarzer into a low save from an acute angle.
Six minutes after the restart Wigan fans were celebrating what they thought was the opening goal when Gomez controlled and struck yards from goal, although the effort only managed to ripple the side netting.
The visitors, though, had begun the second period brightly and Moses tested Schwarzer from long range, before Maynor Figueroa's bouncing effort went well wide.
Fulham fans spent the start of the second half rounding on referee Mason, who was the subject of ironic cheers when he handed Caldwell the game's first booking.
The official's performance could not hide the hosts' poor start, though, and Wigan took the lead in the 57th minute.
Boyce followed up his pass to Sammon and hit an exquisitely-struck shot from 20 yards into the bottom left hand corner.
However, the lead lasted just over 60 seconds as Fulham attacked immediately and Pogrebnyak hit a left-footed effort past Al-Habsi from the edge of the box.
The Russia international thought he had then given Fulham the lead in the 63rd minute when he met Riise's cross, striking an effort which hit the underside of the crossbar and bounced down toward the line.
Pogrebnyak thought the ball had crossed the line, but the officials waved play on having ruled the ball was not fully over.
The 28-year-old again came close in the 77th minute when Dempsey forced Al-Habsi to parry only for Pogrebnyak's follow-up to bobble onto the post and out.
Fulham continued to press for a winner and Senderos almost scored when a Caldwell clearance hit him and flew into the side netting.
The goal would not have counted due to offside but the former Arsenal defender was not to be denied for long, heading home Riise's free-kick in the 89th minute.