Rams boss Nigel Clough demanded a response from his players following the 6-1 thrashing in the Welsh capital, and he got it with Lee Croft and Jay McEveley scoring either side of half-time before Rob Hulse put the icing on the cake with a late penalty.
Clough, whose list of absentees stretches into double figures, made two changes bringing in McEveley for Dean Leacock and handing on-loan Leicester striker Paul Dickov his first Championship start of the season at the expense of Lee Hendrie.
Sheffield Wednesday were unable to call on Luke Varney, who is on loan from Derby, so boss Brian Laws recalled former Ram Marcus Tudgay to his starting line-up.
Both sides were guilty of giving the ball away too easily early on, and it was from such an instance that former Sheffield United striker Hulse headed narrowly wide after 10 minutes.
Croft, who moved to Pride Park on a free transfer in the summer following Norwich's relegation, scored his first goal for Derby seven minutes later.
Dickov was the instigator. The diminutive striker wriggled away from his marker and crossed for Croft to volley home from 12 yards.
Leon Clarke shot wide from close range just before the half-hour mark and Tudgay had a chance with a header in the 41st minute as the Owls threatened.
Dickov almost sent Derby into the break two goals to the good when his shot from the left side of the box struck a post.
Wednesday started the second half brightly with Darren Purse and Michael Gray just missing the target.
However, Laws' side failed to build on their early promise and had Lee Grant to thank for keeping them in the game.
The Owls keeper parried Croft's shot and tipped another effort from Hulse round a post in quick succession just before the hour mark.
Laws brought on Akpo Sodje and Jermaine Johnson soon afterwards, with Clarke and Etienne Esajas the players to make way, and the former nearly made an immediate impact forcing Stephen Bywater to tip his header over the crossbar.
But seconds later, in the 65th minute Dickov and Croft combined to set up McEveley, who scored his first goal since April 2008 with a fine strike from the edge of the box.
Sodje and Purse missed with headers either side of the 80-minute mark before Hulse completed the scoring in the last minute.
Lewis Buxton fouled Hulse inside the area and the big striker picked himself up to score from the spot for his third goal of the season.