A Simon Rolfes equaliser was as good as it got for the Werkself, who were ultimately undone by a Wayne Rooney double and a goal apiece from Robin van Persie and Antonio Valencia, with Ömer Toprak's late consolation failing to disguise a disappointing night's work.
The Premier League outfit looked to assert their home advantage early on, with Dutch international striker van Persie flashing an early effort just past Bernd Leno's left-hand post. Undeterred, Leverkusen responded, but Stefan Reinartz failed to test goalkeeper David de Gea from range.
That rare sight of the hosts' goal aside, Leverkusen found themselves having to do far more defending than they’ve become accustomed to as the half progressed and the pressure soon told when Rooney arrived unmarked to slam Patrice Evra's cross into the turf and over Leno.
Leverkusen almost fell further behind before the half was up as former Borussia Dortmund favourite Shinji Kagawa squeezed a clever ball through to van Persie, whose unselfish attempt to find Valencia was expertly snuffed out by Werkself captain Rolfes. Sami Hyypia's men still weren't out of the woods, but nether Rooney nor Kagawa could convert.
A slick turn and shot from Sidney Sam reminded the English side they wouldn’t quite have things all their own way in the second half, and after Rooney was unable to make the most of a mistake by Toprak, Leverkusen drew level. Heung Min Son did superbly well to hold off his marker and find Rolfes, whose deflected strike left de Gea rooted to the spot.
Parity would not last long, though, with the home side restoring their advantage just five minutes later. Valencia used his pace to get the better of three Leverkusen defenders, before crossing for van Persie to send an unorthodox volley beyond the reach of Leno.
Substitute Lars Bender forced the issue, but within seconds of the Germany international drawing a decent save from de Gea, a mix-up in the visiting back four all but ended the game as a contest as Toprak and Emir Spahic let in Rooney for his second of the night. Valencia added a fourth, before Toprak stabbed home to round off an otherwise unsatisfactory Leverkusen display.
Manchester United: De Gea - Smalling, Ferdinand, Vidic, Evra - Valencia, Carrick, Fellaini (Cleverly, 80'), Kagawa (Young, 70') - van Persie, Rooney (Hernandez, 84')
Bayer Leverkusen: Leno - Donati, Toprak, Spahic, Boenisch - Can, Reinartz, Rolfes - Sam (Kruse, 78'), Kießling (Derdiyok, 78'), Son (Bender, 63')
Goals: 1-0 Rooney (21'), 1-1 Rolfes (53'), 2-1 van Persie (58'), 3-1 Rooney (69'), 4-1 Valencia (78'), 4-2 Toprak (87')