Two goals from veteran striker Steve Howard helped Hartlepool to a surprise 3-2 success at Bramall Lane, ending their miserable 22-game winless run and the Blades' unbeaten home league record.
Lifelong Sheffield Wednesday fan Ritchie Humphreys also found the net for the visitors, with Michael Doyle and Harry Maguire scoring for the hosts, who began the day top of npower League One but slip to second place after this shock defeat.
Bottom-of-the-table Pools took a surprise seventh-minute lead when Howard headed home Evan Horwood's pin-point cross.
Buoyed by that early goal, the visitors put the Blades' defence under pressure for a spell with Howard missing the target after being put through on goal. Jonathan Franks also put an effort off target.
The hosts then enjoyed a good spell of possession with Nick Blackman having a shot on the run saved by Scott Flinders.
But a 30th-minute error from Flinders brought the Blades level, Doyle's 25-yard shot slipping through the goalkeeper's hands and into the back of the net.
Humphreys put Hartlepool back in front with a near-post shot after 54 minutes, George Long got a hand to the ball but could not keep it out.
Howard handed them a two-gaol cushion with a looping header from James Poole's cross in the 72nd minute.
The visitors hung on until stoppage tim when Maguire's 12-yard finish made it 3-2 but it was too little, too late for Danny Wilson's side.