Paul Sturrock's Plymouth cashed in on some dodgy defending to bring his former club's climb up the Coca-Cola Championship table to a juddering halt at Home Park.
Wednesday had lost only one of their previous seven league matches, but Plymouth secured their fourth win in five games thanks to Mark Beevers' own goal and first-half strikes from Paul Gallagher and Jamie Mackie before Marcel Seip's last-minute header.
Brian Laws' Owls travelled south chasing a third straight win after putting their 6-0 thrashing at Reading earlier this month behind them, but an unsettled back four capitulated again in the first period.
While Sturrock fielded the same 11 players who started in the midweek draw at Bristol City, Steve Watson and Beevers returned to Wednesday's defence due to injuries to captain Richard Wood (groin) and Peter Gilbert (hamstring).
Neither side created an opening of any note until Plymouth took the lead in the 15th minute.
Rory Fallon chased a ball in from the left and teenage central defender Beevers, back following a hamstring strain, stabbed the ball past his own goalkeeper Lee Grant.
Argyle stepped up the tempo after their breakthrough and were rewarded with a second in the 25th minute.
Mackie crossed from the right and Gallagher swept home his fourth goal of the season from close range.
The Owls responded when Wade Small drilled in a shot that Romain Larrieu held, but the visitors found themselves three goals down on half an hour after another swift break.
Fallon played the ball in from the right side of the penalty area and Mackie applied the finishing touch from six yards.
Wednesday goalkeeper Grant denied Plymouth a fourth goal, saving well from Fallon's overhead kick.
Owls substitutes Francis Jeffers and Jermaine Johnson replaced Etienne Esajas and Small at the break and both soon went close to pulling one back.
Jeffers fired wide from inside the area, while Johnson was narrowly off-target from 25 yards - but the visitors fell short in their attempts to pull a goal back.
Plymouth weathered the early second-half storm and went close to scoring a fourth when Mathias Doumbe flashed a long-range shot over the crossbar.
Larrieu then parried an angled drive from James O'Connor as the visitors pressed again to reduce the arrears.
Jimmy Smith flashed a volley wide for the Owls and another shot from Johnson was comfortably saved by Larrieu, but it was too little too late for Laws' side, with all the damage being done in the first period.
Smith then headed straight at Larrieu, but Plymouth had the last word when defender Seip leapt highest to head home Luke Summerfield's cross in the last minute.
Teams:
Plymouth: Larrieu, Doumbe, Cathcart, Seip, Barker, Mackie (Paterson 83), Summerfield, Duguid, Clark (Marin 88), Gallagher (Mpenza 90), Fallon.
Subs Not Used: Timar, Folly.
Goals: Beevers 15 og, Gallagher 25, Mackie 30, Seip 90.
Sheff Wed: Grant, McMahon, Beevers, Watson, Spurr, Small (Jeffers 46), O'Connor, McAllister, Esajas (Johnson 46), Burton (Smith 56), Tudgay.
Subs Not Used: O'Donnell, Clarke.
Att: 10,795
Ref: Roger East (Wiltshire).
