The reigning champions knew that victory at the Tottenham Hotspur Stadium - a venue they had lost all of their previous four league visits without scoring - would put them in the driving seat to win an unprecedented fourth successive Premier League title.
After a tense first half, Man City eventually got the job done after the break thanks to two goals scored by leading marksman Erling Haaland, who met a superb De Bruyne cross to tap home his first before converting an emphatically-taken penalty in stoppage time.
Shortly after providing an assist for Haaland's first goal, De Bruyne was seen in discomfort midway through the second half following a nasty, albeit accidental, challenge from Pape Matar Sarr, whose studs dragged down the Belgian's ankle.
Ederson was then on the receiving end of a forceful collision with Cristian Romero at the far post, with the Spurs defender's hip clattering into the head of City's goalkeeper.
Guardiola explains decision to withdraw De Bruyne, Ederson
After a lengthy spell of treatment, Ederson was initially cleared to continue, but he was replaced by Stefan Ortega just a few minutes later, much to the frustration of the Brazilian who was keen to carry on.
Meanwhile, De Bruyne - seemingly still feeling the effects of Sarr's earlier challenge - made way at the same time as Ederson with around 20 minutes remaining, raising concerns over the fitness of both Citizens stars.
With just five days to prepare for Man City's final Premier League fixture at home against West Ham United on Sunday, Guardiola has explained why both Ederson and De Bruyne were taken off in the second half.
Speaking to BBC Match of the Day, the Catalan coach said: "Kevin [De Bruyne] had a kick to the ankle and couldn't run properly. Ederson did not have concussion, he had a problem with his eye.
"He could not see properly so the doctor said I should change. He [Stefan Ortega] is a world-class keeper. He's an exceptional, exceptional keeper."
Guardiola compares title-race finale to Wimbledon
Man City will hope that both De Bruyne and Ederson will be passed fit to feature in Sunday's encounter with West Ham, a contest in which victory for the Citizens will clinch the title at the expense of rivals Arsenal.
Guardiola heaped praise on Tottenham after the match and has quickly shifted his focus to West Ham, comparing City's final fixture to a crucial serve for victory in a tennis match at Wimbledon.
"It was so difficult a game. We knew it. [Spurs] play with a lot of pride and intensity and it's so difficult to play against them," said Guardiola.
"Spurs will in the future be unbelievable if they stick with the manager (Ange Postecoglou). We gave the chance in our hands for the last game. The tennis players say 'the serve to win Wimbledon', the last game, is the most difficult one.
"It happened in our period against Aston Villa (in 2022). And many, many years ago it happened with Sergio Aguero [scoring] in 93 minutes 20 seconds against QPR (in 2012). So there will be the typical game (against West Ham). Now calm, thinking [about Michail] Antonio, [Jarrod] Bowen, [James] Ward-Prowse."
Man City's victory over Spurs has seen them climb to the top of the Premier League table, sitting two points clear of second-placed Arsenal, who face Everton at home in their final fixture of the season.