Off the back of a notable 1-1 draw with league leaders Bayern Munich, Leipzig were ahead after only seven minutes when Andre Silva struck from the edge of the area.
Undefeated in 10 matches after scoring the game's opening goal, the Red Bulls then inflicted further damage on their hosts eight minutes later when Benjamin Henrichs fired into the same corner as Silva for his first league goal of the season.
Making their first appearance at the VELTINS-Arena since the restart, Schalke got off lucky in the 23rd minute as Dani Olmo’s strike was correctly ruled offside.
Leipzig took the match away from their overwhelmed hosts in the 44th minute when Silva was in the right place at the right time to slot Olmo’s blocked effort past the visibly-frustrated Alexander Schwolow.
However, Marco Rose’s side were not finished with their goalscoring escapades before the interval, as Timo Werner added a fourth two minutes later with a sublime finish from close range.
Needing a drastic improvement on their Bundesliga-low 13 goals this season to stand any chance of a sensational second-half comeback, Schalke were handed a glimmer of hope in the 56th minute when Soichiro Kozuki accelerated away from two Leipzig defenders before firing past the onrushing Janis Blaswich.
Set for a fourth successive victory against Schalke, Leipzig should have restored their four-goal advantage as the contest surpassed the hour-mark, only for Henning Matriciani’s last-ditch interception to deny Konrad Laimer a fifth for the visitors.
However, Leipzig did have their fifth seven minutes from time when man-of-the-match Olmo exquisitely lofted the ball into the top corner, and the scoring was concluded six minutes later when second-half substitute Yussuf Poulsen added a sixth.
The one-sided victory lifts RB Leipzig into second position in the Bundesliga standings, three points behind reigning champions Bayern.
In contrast, Schalke remain six points adrift of safety, with the remainder of round 17 still to be played, staring at an immediate return to 2. Bundesliga in the face.
Flashscore Man of the Match: Dani Olmo (RB Leipzig)
