Mueller marked his 400th Bundesliga appearance by opening the scoring with his 222nd league goal before defender Upamecano, signed from Leipzig for this season, headed in his first goal in the famous red Bayern shirt.
Leroy Sane then planted a shot into the left corner on the hour mark.
Lewandowski, who on Tuesday equalled Gerd Mueller's record of 42 German league goals in a calendar year from 1972, capped a gala night with Bayern's fourth to claim the new record outright.
This was Bayern's final match before the Bundesliga winter break and head coach Julian Nagelsmann was pleased with the performance.
"We defended well, pressed them hard, won pretty much every ball in our own half and we deserved to win by that margin," said Nagelsmann.
The Bayern boss also praised Lewandowski's latest record, "he really deserves it, especially as he scored with his weaker foot".
Bayern's lead at the top of the Bundesliga table can be trimmed on Saturday by second-placed Borussia Dortmund, who are away to Hertha Berlin.
This was Wolfsburg's seventh straight loss, piling the pressure on new head coach Florian Kohfeldt who only took charge at the end of October after the sacking of predecessor Mark van Bommel.
"That hurts - we defended badly, especially for the fourth goal, that wasn't on," fumed Kohfeldt who now has the two-week break to drill his team.
In contrast, this was Bayern's seventh straight victory in all competitions.
Bayern were ahead after only seven minutes behind closed doors at the Allianz Arena when Serge Gnabry's thunderbolt shot from distance was parried into the path of Mueller, who tapped home.
It stayed 1-0 at the break, but Mueller's deft chip gave him a 15th assist in the Bundesliga this season as Upamecano steered his header into the net.
Just three minutes later, Sane grabbed Bayern's third when he unleashed a superb shot which gave Wolfsburg goalkeeper Koen Casteels no chance.
Lewandowski finally got the goal to break another of Gerd Mueller's records with some deadly finishing.
Before kick-off, Bayern sports director Hasan Salihamidzic ruled out any new signings in the forthcoming January transfer window.
"We are really well-staffed, that's a fact," he stressed, "we will continue as things are this season."
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