The Citizens, back in action four days on from suffering their first domestic defeat of the season, require just a point at the Etihad Stadium to secure top spot in Group F as focus turns back to their European campaign.
Chelsea showed with their 2-0 win on Saturday evening that Man City can be beaten with the right tactics - and a little bit of fortune - as the champions suffered their first loss in the Premier League since April.
It also marked the first time that Pep Guardiola's men had lost by more than two goals since going down 4-0 to Everton in January 2017, with goals from N'Golo Kante and David Luiz at Stamford Bridge ensuring that the title race remains alive heading into the Christmas period.
Liverpool's win at Bournemouth earlier in the day means that City now trail the new pacesetters by a point, though City remain the favourites with many to finish top, which would make them the first side in a decade to successfully defend their crown.
The league games against Everton, Crystal Palace, Leicester City and Southampton over the next three weeks have now taken on added significance, but Guardiola cannot take his eye off the ball in Europe as top spot has yet to be nailed down in Group F.
City have responded strongly to a huge setback on matchday one in the Champions League, when suffering an unexpected home loss to Lyon, by overcoming Hoffenheim 2-1 in Germany and seeing off Shakhtar Donetsk 3-0 and 6-0 in their recent double-header.
Last month's 2-2 draw with Lyon, responding twice through goals from Aymeric Laporte and Sergio Aguero, was therefore enough for Guardiola's charges to make certain of a place in the last 16, and now they simply have to avoid defeat at home to Hoffenheim to finish first.
Even defeat may not stop City from coming out on top, though, as Lyon must win away at Shakhtar in the other Group F match on Wednesday to close the three-point gap.
Guardiola will no doubt be targeting all three points in midweek, however, knowing that victory will help to regain some momentum while also setting up a favourable first knockout round tie in March.
Recent form in Champions League: LWWWD
Recent form (all competitions): WWDWWL
With their debut Champions League group campaign drawing to a close, the best Hoffenheim can hope for ahead of the final round of matches is a third-place finish.
For that to be achieved, Die Kraichgauer must pick up a shock victory at the Etihad Stadium and hope that Shakhtar - two points better off in third - lose at home to Lyon.
Hoffenheim's three group points have come via draws, having held Shakhtar in Ukraine and played out back-to-back stalemates with Lyon. If not for a couple of late equalisers from Lyon in those two fixtures, it may well have been the Germans in a straight shootout with City for top spot.
As it is, though, a late loss in their home meeting with Shakhtar two weeks ago has left them holding out for a place in the Europa League, which would still be considered a good achievement for young boss Julian Nagelsmann.
Having finished a club-record third in the German top flight last season, Hoffenheim have struggled this time around as three successive draws have left them down in seventh place, albeit just three points off the top four.
Including the cruel loss to Shakhtar last time out in this competition, Nagelsmann's men are now winless in four matches in all competitions since November 10. In Europe, meanwhile, they are stuck on one win from their last 13 games home and away.
Hoffenheim have both scored and conceded at least once in all of those games, with a combined 22 goals being netted in their five group matches to date.
Three losses in their last nine European matches suggests that Die Kraichgauer may be difficult to shake off, but they have never won away from home on the continent and a point simply will not do on Wednesday. The visitors' Euro hopes, it seems, are coming to an end.
Recent form in Champions League: LDLDDL
Recent form (all competitions): DWDLDD
City still have work to do in their Champions League group, but amid a tough run of fixtures Guardiola will surely make some changes.
Nicolas Otamendi is in line for a return in the heart of defence, either in place of John Stones or Laporte, while Gabriel Jesus - in desperate need of a goal to boost his confidence - is also likely to be welcomed back in the absence of Aguero.
In terms of the visitors, Belfodil returned to the scoresheet in the 2-2 draw against Wolfsburg at the weekend, ending a run of six matches without a goal.
Croatia international Kramaric has scored in his last eight games for club and country, including the equaliser against Wolfsburg to keep Hoffenheim in the hunt for a top-four finish.
Manchester City possible starting lineup:
Ederson; Danilo, Otamendi, Laporte, Delph; Foden, Fernandinho, Gundogan; Mahrez, Jesus, Sane
Hoffenheim possible starting lineup:
Baumann; Bicakcic, Vogt, Hübner, Kaderabek; Zuber, Demirbay, Schulz; Kramaric; Belfodil, Joelinton
Head To Head
Man City came from behind to beat Hoffenheim 2-1 on matchday two in what was the Bundesliga side's first home group game in the competition.
The Citizens have won six of their nine home games against German clubs, scoring 11 goals in their last three such matches, while Hoffenheim lost 6-3 on aggregate to Liverpool in the playoffs last season in their only previous tie against English opposition.
We say: Manchester City 3-1 Hoffenheim
The Citizens have still not quite taken to European football, despite the arrival of two-time Champions League-winning manager Guardiola. City have won just four of their last 10 matches in the competition, losing half of those, but they come up against an out-of-form Hoffenheim side requiring just a point to go through as group winners. Anything other than a straightforward home win would be a surprise.