The Citizens are top of the Premier League, into the last eight of the FA Cup and have an EFL Cup final against Chelsea to look forward to later this week, but all focus now is on progressing in Europe.
Schalke had little trouble holding down a top-two spot in Group D, finishing seven points better off than Galatasaray after losing just one of their six matches - a 3-1 loss to Porto on matchday five.
The German side have made it through to the first knockout round and no further in each of their last three Champions League campaigns, most recently being dumped out by winners Real Madrid in 2015 after putting up a brave fight over the two legs.
Matching their achievement of 2010-11, when reaching the semi-finals of the competition, is surely out of the question this time around as they have struggled for form all season.
Last term's runners-up in Bundesliga have 27 points after 22 games of this season. Rather than looking up at the European spots, Schalke are in a battle to avoid the drop, finding themselves only two places above the dropzone in 14th.
Schalke have already lost 11 league matches in 2018-19, compared to seven throughout last season, and they are without a win in the last month. Competing in the knockout rounds of the Champions League could be seen as a welcome distraction, then, though any sort of heavy defeat to Man City will only further dent the Royal Blues' confidence.
Domenico Tedesco's side should not be written off just yet, though, as they are unbeaten in their last nine European home games, winning six of those. They last went on a longer run without a home defeat between July 2003 and November 2004 (11 games).
Schalke are also looking to win three consecutive home Champions League games for the first time since April 2011 when reaching the semi-final of the competition, having beating Galatasaray and Lokomotiv Moscow in their last two outings at the Veltins-Arena.
Their progression to the last 16 came despite a lack of cutting edge in attack, scoring just six goals in the group stages - the lowest tally among the 16 clubs left in the competition, with five of those six goals coming after half time.
No Schalke player scored more than one goal or delivered more than one assist in the group phase, though only Borussia Dortmund (5) kept more clean sheets than the Royal Blues (4). In Man City, though, the German club's defence face by far their toughest test yet.
Recent form in Champions League: DWDWLW
Recent form (all competitions): WDLWLD
Although they were perhaps made to work harder for the victory than expected, Man City kept alive their hopes of a clean sweep of trophies by seeing off Newport County 4-1 in the FA Cup fifth round on Saturday.
That made it four wins in a row for the Citizens in all competitions and 12 wins in their last 13 matches since losing back-to-back games over Christmas to dent their Premier League title hopes.
Pep Guardiola's men, a blip at Newcastle United aside, have responded to those defeats against Crystal Palace and Leicester City in a ruthless manner. In their 13 matches since then, 48 goals have been scored and six conceded.
Despite the manager's best efforts to play down talk of a quadruple, there is no doubt that City are well positioned to achieve something that no other English club has managed in the modern day by winning all four competitions that they are a part of.
The EFL Cup final clash with Chelsea next week offers the reigning English champions a chance to tick off one of those trophies, but Guardiola is not the type of person to take his eye off the ball for a second. The biggest priority right now is Wednesday's trip to Schalke, with City being given the chance to take a big step towards reaching the last eight.
Guardiola may have won the trophy twice as a manager at Barcelona, but he has fallen a fair way short during his two full seasons at the Etihad Stadium. After crashing out to Monaco at this stage in 2017, City marginally improved by reaching the quarters last time around, where they were dumped out by domestic rivals Liverpool.
City have lost five of their eight Champions League knockout games away from home, beating only Dynamo Kiev and Basel in that time. They were also held to a 2-2 draw by Lyon in their most recent away match in the competition and suffered a 2-1 reverse to the same opponents on matchday one at the Etihad Stadium.
The Citizens recovered in quite some style from their opening-match setback by taking 13 points from the next 15 on offer, seeing them finish well clear at the top of Group F, and Guardiola will now be hoping that his players can learn from the last two seasons by advancing to the semi-finals and beyond.
Recent form in Champions League: LWWWDW
Recent form (all competitions): WLWWWW
Guardiola made seven changes between the wins over Chelsea and Newport, including a seventh start of the season for Phil Foden, who was City's star man at Rodney Parade.
Foden is unlikely to have done enough to displace Kevin De Bruyne, Fernandinho and David Silva from central midfield, however, and there are no suggestions that Guardiola is going to field a weakened side ahead of the EFL Cup final.
Bernardo Silva has performed well in an advanced position on the right of City's front three and is expected to start again on Wednesday, which could mean Leroy Sane being named as a sub against his former club.
In terms of the home side, Rabbi Matondo was handed his first start in the goalless draw with Freiburg at the weekend, a month after joining from Man City.
The young Wales international will have a point to prove against his former club, but he may have to settle for a place on the bench as Yevhen Konoplyanka is in contention to return in attacking midfield.
Rumoured City target Rudy should start in defensive midfield, sitting in front of another former Citizens player in Matija Nastasic, who is now into his fourth full season at the Veltins-Arena.
Schalke 04 possible starting lineup:
Fahrmann; Caligiuri, Sane, Nastasic, Oczipka; Bentaleb, Rudy; Uth, McKennie, Konoplyanka; Burgstaller
Manchester City possible starting lineup:
Ederson; Walker, Stones, Laporte, Zinchenko; De Bruyne, Fernandinho, D.Silva; Bernardo, Aguero, Sterling
Head To Head
Schalke and Man City are facing each other in a third different European competition after also meeting in the Cup Winners' Cup in 1970 and the UEFA Cup in 2008.
City beat Schalke 5-2 in the semi-final of the first of those competitions and went on to win their first and so far only European trophy, beating Gornik Zabrze 2-1 in the final.
More recently, the Citizens claimed a 2-0 triumph in Gelsenkirchen in the UEFA Cup group stage more than a decade ago thanks to goals from Benjani and Stephen Ireland. Kompany played 90 minutes for City that day - the only player from either side who is still with their club.
We say: Schalke 04 0-2 Manchester City
Man City, unbeaten in their last seven Champions League games against German opposition, have been handed a favourable last-16 tie as Schalke have been poor this season and tend to struggle at this stage of the competition. The hosts' impressive defensive record on the continent does at least offer a little hope that they can keep things tight ahead of the return match next month, but City will still fancy their chances of scoring an away goal or two.
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