Sheffield Wednesday striker Gary Madine took his tally to 14 goals this season as Notts County lost for the first time under Keith Curle.
Michail Antonio beat two players to cross for Ryan Lowe to tap home inside the six-yard box to put the Owls ahead.
Lewis Buxton then set up Madine to fire into the bottom left-hand corner.
Notts pulled a goal back as substitute Lloyd Sam, who signed on loan from Leeds in midweek, got the final touch to an Alan Judge free kick.
The Owls, who completed their first double over Notts for 99 years, stay third but move level on points with rivals Sheffield United, who could only draw 1-1 with Tranmere.
Wednesday stretch their unbeaten run under new manager Dave Jones to four matches and have now won three in succession.
Notts stay just inside the play-off places in sixth but Curle tasted defeat for the first time in seven matches since taking over from Martin Allen in mid-February.
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