Wigan Athletic 1 Tottenham Hotspur 0
It was the first time the £15million striker has failed to score on his debut for any of his clubs.
But despite creating the lion's share of the chances and dominating the game for long periods, it looked like Wigan would have to settle for a share of the points.
But the Honduran defender clinched the Latics' fifth straight home win after heading home from a Ryan Taylor corner.
It was all change for the Latics with Steve Bruce recalling his big guns including Amr Zaki and birthday boy Emile Heskey after last week's FA Cup exit at White Hart Lane.
For Spurs, all eyes were on Defoe after his return ticket from Portsmouth was finalised on Friday.
Wigan survived a sloppy start after needlessly giving away possession from the kick-off and Chris Kirkland was forced into early action keeping out a Ledley King header from a Jamie O'Hara free-kick and reacting well to deal with Michael Dawson's follow-up.
O'Hara sliced another chance just wide when Luka Modric slipped the ball to him inside the box and Kirkland had no problem dealing with a Jonathan Woodgate header.
Wilson Palacios conjured up Wigan's first threat by winning the ball from Didier Zokora to send Amr Zaki racing through, but Michael Dawson get in the vital block as the striker let fly.
Ryan Taylor just cleared the bar with a fierce free-kick and, after Gareth Bale was fortunate to escape with a yellow card for his tackle on Antonio Valencia, Zaki was inches wide from breaking the deadline with a header.
Palacios tried his luck with a spectacular overhead shot but Heurelho Gomes was perfectly positioned to hold it and the keeper again came to the rescue blocking a Heskey effort after a terrific break by Zaki.
But Spurs wasted a chance after catching Wigan on the break. Defoe set it up for Zokora but he hammered well wide.
A Valencia break spelled more danger for Spurs as Wigan continued to apply the pressure in the second half but the delivery was crucially deflected out of Heskey's path.
Wigan had another chance from a Taylor free-kick but it lacked his usual accuracy and both Zaki and Heskey failed to get headers on target.
But in stoppage time, Figueroa struck with a powerful header from another Taylor corner to the delight of the JJB Stadium faithful.