Roberto Soldado scored twice, while Juan Mata, Aritz Aduriz, Joaquin and Alejandro Dominguez added the rest against a poor Bursaspor side, who scored their first goal of the group in the 68th minute when Pablo Batalla made it 5-1.
Valencia are three points behind leaders United who they visit on December 7, and a win would leave them top.
"The objective obviously was to qualify for the last 16, but we want to do it as first in the group," Valencia coach Unai Emery told reporters.
"We have the chance to do it in a memorable setting (Old Trafford) and against a side who beat us here at the Mestalla.
"We have to think in the short term. The team has the capacity to go far but we aren't setting any concrete objectives."
Reaching the knockout round is a feat in itself and seemed barely likely when they started the season back in August.
The side had just sold Spain duo David Villa and David Silva to Barcelona and Manchester City respectively, and offloaded Carlos Marchena, Ruben Baraja and Nikola Zigic among others to help finance their crippling debts.
In came a handful of lower cost signings but two of those, strikers Soldado and Aduriz, have quickly settled in while young Spain winger Mata, 22, is flourishing with the increased responsibility.
It was Aduriz who was brought down for a penalty in the 17th minute and Mata stepped up to open the scoring from the spot.
SOLDADO'S FIFTH
By then, however, Bursaspor should have been in front. The side who had lost 4-0 at home to Valencia two months ago, broke away in the 12th minute but with only Miguel Moya to beat Sercan Yildirim lifted his lob just wide of the post.
Valencia doubled the lead in the 21st with a well-worked move down the right flank, Aduriz pulling back for Mata who played Soldado in behind the defence to score in the far corner.
Jordi Alba crossed low for Aduriz to make it 3-0 at the second attempt in the 30th and Joaquin curled a shot into the top corner before the break.
Soldado grabbed his fifth of the competition, breaking clear to round Dimitar Ivankov and score from a tight angle in the 55th.
Bursaspor substitute Batalla got on the end of Yildirim's cross to score, but the ball was soon back down the other end and after a long clearance was flicked on Dominguez scored Valencia's sixth in the 78th.
Bursaspor coach Ertugrul Saglam said: "There isn't much to say it has been a heavy defeat, the only person responsible is me, the players did what they could. I apologise to the fans who travelled with us here."
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