Last season, the 33-year-old midfielder was forced to sit out due to a hamstring injury until the beginning of 2024. However, this season he has been a consistent presence on the field, starting all but one game so far.
This included the Champions League match against Serie A giants Inter Milan on Wednesday, although the player was withdrawn at the interval after feeling discomfort in the first half.
De Bruyne appeared to grab his groin when the cameras panned to him grimacing while still on the pitch. The Belgian playmaker did not re-emerge from the tunnel after the break and was replaced by veteran Ilkay Gundogan.
"I don't know, I haven't spoken with the doctors yet," Pep Guardiola said during his press conference when asked about De Bruyne's setback. "I will have more information when I do. We will assess him tomorrow (Thursday)."
TrendingGiven the injury and his early exit from the game, it is clear De Bruyne is now a major doubt for the heavyweight clash against fellow title contenders Arsenal, live on on Sunday.
City have coped well without their main midfielder in the past - but this time it feels particularly significant, as interest from the Saudi Pro League and his expiring contract continue to loom over the situation.
His current deal is set to expire next summer and he has been vocal about the possibility of pursuing another challenge - such as the Middle East - in the past.
"At my age you have to be open to everything," De Bruyne told Belgian outlet Het Laatste Nieuws during the summer window.
"You're talking about incredible amounts of money in what may be the end of my career. Sometimes you have to think about that.
"If I play there for two years, I will be able to earn an incredible amount of money. Before that I had to play football for 15 years. I may not even reach that amount yet."
With De Bruyne seemingly willing to consider the move, and his contract continuing to run down, the game against Arsenal could offer an insight into what life at the Etihad will look like without him at the club.
De Bruyne's impact after returning from injury last season, with four goals and 10 assists on the way to a record fourth league title in a row for City, showcased the player is still at the height of his powers - but this will not always be the case.
City's recent recruitment, as well as the immense firepower they already had within the squad, has set them up well for the future.
Gundogan, Phil Foden, Jack Grealish, Matheus Nunes, Bernardo Silva, Mateo Kovacic and the injured Oscar Bobb give Guardiola options to turn to for creativity - with Grealish's new England role under interim boss Lee Carsley possibly arriving at the perfect time.
During his last absence, Foden or Julian Alvarez, who has since left for Atletico Madrid, were often the ones to be deployed in his position and impressed while doing so, with the former securing the PFA Player of the Year award thanks to his performances throughout the campaign.
The England international has endured a disjointed start to the new season, after suffering with illness, but made his second appearance of the campaign against Inter and will be crucial in both the immediate and long-term futures of the team - especially if his Belgian team-mate departs.
Foden has grown from strength to strength since rising through the City academy but with seniors such as De Bruyne, Sergio Aguero, David Silva and Vincent Kompany always ahead of him, the team has never felt like his own.
However, his 19 goals and four assists in the top flight last season, which included an inspiring hat-trick during a 4-1 comeback victory against Aston Villa in the absence of De Bruyne, proved he is capable of taking the reins at the club.
' Paul Merson:
"Thing is, Kevin De Bruyne is a big miss and they missed him a lot of last season - but they still won the title. You have Foden and Gundogan coming on, it's phenomenal really.
"I loved the game [vs Inter Milan]. It was a proper football match. Inter Milan were outstanding defensively and Man City had to be patient, but they still made three or four clear-cut chances.
"De Bruyne will be missed but they have players who can take his place - it's a bit different to the Arsenal one with [Martin] Odegaard.
"I think Gundogan will play and Kovacic will play, in my opinion. They have such riches to pick from, Foden, Gundogan and [Jeremy] Doku. Rodri is back in the team. So, so many options. There is no one better than Guardiola to get it right."