City defeated United 2-0 at Old Trafford as second-half goals from Bernardo Silva and Leroy Sane made the difference.
The win allowed City to leapfrog Liverpool back into first place in the Premier League, and they will guarantee a second straight title with wins in their final three games of the season.
City boss Guardiola also made some personal history with the victory, as the Spaniard is now the first manager to win three consecutive away Premier League matches at Old Trafford against United.
Only Arsene Wenger and Gerard Houllier join Guardiola as managers to win three total away matches at Old Trafford.
The win also meant City have now won seven Premier League games against United at Old Trafford – more than any other team.
City reached a team milestone during the game as well, setting a new Premier League goalscoring record across all competitions.
For United, it was another poor result in a season that is rapidly unraveling after a mid-season renaissance under Ole Gunnar Solskjaer.
Following his December appointment in place of Jose Mourinho, Solskjaer guided his side to a run of 14 wins in 17 games overall.
But Man Utd have now followed that run with a stretch of seven defeats in nine matches.
The club have also failed to keep a clean sheet in 12 straight games in all competitions – the first time since August 1971 that United have endured such a run.