Stuart Beavon's goal gave Wycombe their first victory in six league games as Sheffield United suffered a rare loss.
Wycombe had not scored in the league since 16 August but Beavon ended that run with a well-struck effort from 15 yards after Harry Maguire's mistake.
Ched Evans had the best chance for the Blades, but his shot from 25 yards hit the bar as the visitors lost their first away league match of the season.
Joel Grant nearly doubled the hosts' lead but shot wide when well-placed.
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Sheffield United boss Danny Wilson told BBC Radio Sheffield:
"It was a fantastic performance, there's only one thing we can say and that's we didn't put a ball in the net.
"They'll say they defended well, but I think they had a bit of luck on their side as well.
"We completely dominated from start to finish, so we're going to be disappointed of course. But we'll take the frustrations out next week against Charlton."