Rushden started well and on five minutes a good turn by Drewe Broughton created a chance but his shot was easily saved by Frank Talia.
On 12 minutes Ian Stonebridge had a free header following a Clint Easton cross but his header went wide.
Wycombe keeper Talia almost took the ball over his own line on 15 minutes following Darren Caskey's free kick.
Wycombe full back Danny Senda hit a tremendous shot from 30 yards but Scott Tynan produced a brilliant save.
On 21 minutes John Turner saw his shot blocked and a minute later Tony Stokes tested Talia with a shot.
Rushden took the lead on 24 when Marcus Kelly stole in from the left to head home Turner's pin-point cross.
On 31 minutes Wycombe's Russell Martin almost chipped Tynan but the keeper recovered to tip over.
On 48 minutes Caskey cleverly chipped just over and a minute later the visitors had a good chance but Martin shot across the face of goal when well placed.
On 61 minutes Wycombe levelled when veteran striker Tommy Mooney struck from close range from a Kevin Betsy cross.
Wycombe took confidence from the goal and went in front three minutes later when Stonebridge crossed for skipper Roger Johnson to score from eight yards out.
Rushden sacrificed their defensive responsibilities to get level and, on 81 minutes, Caskey's free-kick went inches wide. Two minutes later Betsy created a good chance when he pulled the ball back to Mooney who blasted over.
Wycombe sealed the win on 88 minutes when Matt Bloomfield was fouled by Rob Gier and in doing so the Rushden skipper was dismissed for a second yellow card. From the resulting penalty Mooney tucked the ball home.