Pep Guardiola's side are already through to the knockout stages as Group A winners following a 2-1 win over Paris Saint-Germain last month.
And City can therefore afford to rest a number of their key stars and give youngsters some valuable minutes for the behind closed doors clash.
RB Leipzig v Man City: Date and kick-off time
This Group A clash will take place on Tuesday, December 7.
It will be held at the Red Bull Arena in Leipzig with a UK kick-off time of 5:45pm.
City won the reverse fixture 6-3 back in September with Jack Grealish scoring his first ever Champions League goal during his first start in the competition.
RB Leipzig v Man City: talkSPORT commentary
This game will be broadcast on talkSPORT 2 with coverage starting at 5:30pm.
Commentary will come from Joe Shennan and former Manchester City defender Danny Mills.
Coverage of Real Madrid's clash with Inter Milan will then follow the end of this match on talkSPORT 2.
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RB Leipzig v Man City: Team news
Tyler Adams is back from a Champions League suspension for the hosts but Ilaix Moriba and Amadou Haidara are both out of contention.
Leipzig also have a number of other injury concerns with Yussuf Poulsen joining Dani Olmo, Marcel Halstenberg and Marcelo Saracchi on the sidelines.
Willi Orban and Hugo Novoa were still self-isolating as well due to coronavirus protocols before the defeat against Union Berlin.
As for City, Guardiola can welcome back De Bruyne after the midfielder came on as a substitute in the win at Watford at the weekend.
Ferran Torres remains the visitors' only injury concern as Guardiola hinted at giving his young players some first-team minutes.
"We have an incredible academy," Pep said.
"The first team is important. For them (young players) it's an incredible experience in Europe, to see how opponents behave. Maybe tomorrow some can play minutes. We have five substitutions and maybe we can use them."
RB Leipzig v Man City: What has been said?
Guardiola defended De Bruyne's form this season after revealing the Belgian will start against Leipzig following his comeback from coronavirus.
He said: "Kevin was growing in his physical condition and then he had the setback.
"People who have suffered coronavirus, after they feel empty. Step by step he will play the minutes. Tomorrow he will start.
"Kevin played the season from the beginning. He arrived from Euros and last season, not in good condition and then had coronavirus.
"We've got him back, fighting for a position like everyone. He doesn't have to show me anything, just to show he's back and himself.
"Do what he can do for the last five years. He's so necessary for the team. Bernardo and Gundogan know it, you have to be good for 90 minutes."