Rushden started well and on three minutes Drewe Broughton saw his header go inches over following David Bell's corner.
On 15 minutes Broughton was again in the thick of the action with a fierce shot from 20 yards which again was inches over.
Rushden's Billy Sharp made a strong run in the 20th minute, but his shot flew just wide.
On 34 minutes Frank Talia made a fine save to deny Sharp, but three minutes later Rushden suffered a blow when central defender Phillip Gulliver was forced to leave the field with a leg injury.
A bad clearance by Rushden keeper Lee Worgan almost let in Steve Claridge, but he was denied by a saving tackle from substitute John Dempster.
Talia was lucky not to be sent off on 48 minutes when he received only a yellow card after handling outside the area. From the resulting free kick Talia made a fine save from Bell.
Rushden then took the lead in the 51st minute when Neil McCafferty fed Bell on the left, and his cross was headed home by central defender Graham Allen.
Rushden should have increased their lead on 61 minutes when Andy Burgess fired just wide after Broughton's cross had been flicked on by Sharp.
They were made to pay for that miss when Wycombe equalised with their first shot on target as substitute Matt Bloomfield hit a screamer past Worgan form 25 yards out.
Rushden retaliated in the 79th minute when Burgess was inches wide, before substitute Alex Hay almost put Rushden in front when set clear on goal, but Talia blocked his shot well.
It looked to be the final chance of the game, but a minute into injury time, Wycombe scored an undeserved winner when Rushden were caught napping and Nathan Tyson fired in.