A sensational second-half performance from Carlisle ended Sheffield Wednesday's seven-match unbeaten run.
The Cumbrians hit three goals in 15 minutes after Ben Marshall's fine run and shot had given the Owls the lead.
Lee Miller slid home from close range and Rory Loy blasted home before Liam Noble made it 3-1 with a cool finish.
Former Carlisle striker Gary Madine was dismissed for collecting two yellow cards before Rob Jones headed in a consolation for the visitors.
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Carlisle United boss Greg Abbott told BBC Radio Cumbria:
"It's a wonderful feeling. Football's about enjoying yourself and living the dream.
"It's nights like this that are special, under the lights. I think we had one against Wednesday in the Johnstone's Paint Trophy, but our quality of football tonight was even better and the edge with it being a league game was higher.
"It's hard to compete with teams like Sheffield Wednesday with their team, their money and resources, and we competed. We're pushing ourselves against people with miles bigger resources and done ourselves a tremendous credit."