Pep Guardiola's team thumped Brighton 4-1 away to finish on 98 points - the second-highest total in Premier League history - as Liverpool beat Wolves 2-0 at Anfield to finish a single, agonising, point adrift.
City, who strung together 14 league wins at the end of the season, are the first side to retain the title since their bitter rivals Manchester United managed the feat in 2009, and remain on course for the first domestic treble in English football history.
But Guardiola's team of aristocrats did not have it all their own way on a day of drama on England's south coast in keeping with an astonishing season in which the lead switched hands time after time.
Liverpool drew first blood on Sunday, with Sadio Mane striking in the 17th minute to put them mathematically top of the table and on course for their first English top-flight title since 1990, before the Premier League era even started.
City fans' nerves were shredded even further when Glenn Murray put Brighton in front from a corner in the 27th minute, resulting in a huge roar at Anfield.
But those cheers were quickly muted, with Guardiola's side level just 83 seconds later, Aguero staying onside and keeping his cool to finish after a brilliant ball from David Silva.
Ten minutes later, the unmarked Aymeric Laporte rose to head in Riyad Mahrez's corner to complete the turnaround for City.
Guardiola's side continued to dominate at the start of the second half and were rewarded when Mahrez smashed in a third goal with 27 minutes to go.
Ilkay Gundogan then blasted home a free-kick to put the result beyond doubt.
- Record-breakers -
City broke a host of Premier League records in romping to the title last season, becoming the first team in English top-flight history to reach 100 points and finishing a record 19 points clear of closest rivals Manchester United.
This term has been a totally different campaign, with Guardiola's men forced to dig deep to see off the relentless challenge of Liverpool, who have lost just one Premier League game all season.
The champions have ground out a number of 1-0 victories in recent weeks, showing they have added steel to their style.
The outcome was cruel on Liverpool, who are second behind only United in the all-time list of English champions with 18 titles, although the last came in 1990.
The Merseysiders' points tally is the third-highest in Premier League history.
Jurgen Klopp's side travelled to face City at the Etihad in January with the chance to open up a 10-point lead but the defending champions won 2-1 in what turned out to be the pivotal match of the campaign.
Liverpool suffered a blip in late January and February, held to a series of draws, but they found their form again and relentlessly harried City, finishing with nine straight league wins.
Klopp's team will have to put the disappointment behind them as they prepare to face Premier League rivals Spurs in the Champions League final in Madrid on June 1.
Elsewhere on the final day of Premier League action, Tottenham made mathematically certain of a place in the top four, drawing 2-2 against Everton.
Arsenal beat Burnley 3-1 while fellow Europa League finalists Chelsea were held to a goalless draw at Leicester.
Ole Gunnar Solskjaer's Manchester United finished their season with a whimper, losing 2-0 at home to relegated Cardiff.
There were also wins for Crystal Palace, Newcastle and West Ham. Southampton and Huddersfield drew 1-1.
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