The Red Devils really got going in the second half as they netted three times, but conceded twice, to kick off their 2013/14 European campaign with a comfortable win.
Rooney opened the scoring in the 22nd minute when he slotted home Patrice Evra's cross with a first-time effort before captain Simon Rolfes equalised for Leverkusen ten minutes into the second half by curling Heung Min-son's weighted pass into the back of the net with the help of a deflection off Michael Carrick.
United reclaimed the ascendency just before the hour-mark with van Persie scoring in fine fashion with a semi bicycle kick from Valencia's cross before Rooney notched his milestone goal with 20 minutes remaining, getting on the end of a long David de Gea ball, which fell to the striker from Emir Spahic's header, to simply finish past Bernd Leno.
Valencia got in on the act in the 79th minute when he netted his first goal in Europe in almost two years before Omer Toprak pulled one back for the Germans with two minute s left as de Gea failed to clear.
The win would have United feeling confident about their chances in their group this season, especially seeing as Shakhtar Donetsk accounted for Real Sociedad 2-0 in Spain, showing it could be a very one-sided affair in Group A.