The Championship side put a much-changed Gunners team to the sword at Hillsborough, with Theo Walcott and Alex Oxlade-Chamberlain both limping off with first-half injuries
Ross Wallace, Lucas Joao and Sam Hutchinson scored to make it a night to remember for the hosts and left Arsenal rueing the loss of Alex Oxlade-Chamberlain and Theo Walcott to injury.
Buoyed by a fine recent run, Arsene Wenger named an experimental XI featuring the likes of Glen Kamara, Alex Iwobi and Joel Campbell, with only Oxlade-Chamberlain, Petr Cech and Olivier Giroud retaining their place from the side that beat Everton on Saturday.
The Frenchman was left scratching his head before 20 minutes had passed, though, as first Oxlade-Chamberlain and then the man who replaced him, Walcott, were both forced off with suspected muscle injuries.
Oxlade-Chamberlain lasted just five minutes before Walcott, who initially attempted to play on, was withdrawn for Ismael Bennacer a quarter of an hour later.
And Wenger's expression was considerably more pained by half-time, with Wednesday 2-0 ahead thanks to excellent goals from Wallace and Joao.
They took the lead in the 27th minute when Daniel Pudil worked his way down the left wing before sending in a superb low pull-back that Wallace expertly curled into the bottom corner.
Carlos Carvalhal's men continued to look a threat thereafter and almost grabbed a second when Jeremy Helan wriggled through on goal and forced a good save from Cech.
The goalkeeper was powerless moments later, however, as Wallace sent in a delicious centre that Joao nodded home.
Whatever Wenger said to his side at half-time hardly had the desired effect, as the buoyant hosts added a third six minutes after the restart.
Barry Bannan delivered a lovely free-kick to the back post, with Tom Lees - who looked marginally offside - sending a controlled volley across goal for Hutchinson to poke home.
Not content with three, Wednesday continued to push forward and almost netted again when Joao nodded narrowly wide from Bannan's centre.
Arsenal did not force goalkeeper Joe Wildsmith into a difficult save until the 70th minute, when Per Mertesacker saw his close-range header turned over the crossbar.
It proved the only real moment of Arsenal resistance as Wednesday cruised to victory.