In a game of few chances, City held firm for the most part and were rarely troubled by the home side. but the one time when Brentford managed to get in behind the Blues' backline, Ethan Pinnock prodded home with five minutes remaining.
On a sunny, warm afternoon at the Gtech Community Stadium, a much-changed City took on a Brentford side who still harboured Europa Conference ambitions.
For that to happen, they needed to win this game and Aston Villa to draw at best at home to Brighton.
None of that was City's concern, however, and Cole Palmer almost gave his side the lead inside four minutes with a low shot from 12 yards that David Raya did well to palm out.
The Bees occasionally threatened with Ederson forced into a smart save from Ben Mee's snap shot on 36 minutes.
The Blues ended the half with a Julian Alvarez header that went a foot wide in a game that had failed to catch light as yet.
The Bees came out after the break with more intensity and purpose, which was only to be expected.
The news Spurs and Villa were winning their games had filtered through to the home support, but there was no less desire to beat the Premier League champions and complete an unlikely double over Guardiola's men.
The Bees huffed and puffed, but carried little threat in front of goal.
With the Brentford fans appealing for anything and everything, the atmosphere cranked up as the Bees built up a head of steam ias the half wore on.
One decision that infuriated the home players, manager and supporters came when Ben Mee and Rico Lewis went to ground in the City box with Mee's prod at the ball rolling against the falling Lewis' arm - the referee got it right, however, with Lewis unable to get his arm out of the way and no penalty was awarded.
Then, in what was increasingly a rare City attack, Palmer collected a long ball on the edge of the box and as Raya raced out, his attempted lob was easily plucked out of the air by the Brentford keeper.
With just five minutes remaining, it was Brentford who finally broke the deadlock.
The Bees broke down the right flank and a dangerous cross found the head of Mbeumo who guided the ball back to Ethan Pinnock who placed a low shot past Ederson to give the home side the winner.
City should have levelled in the last minute when Palmer had two terrific chances within a couple of seconds, first seeing a powerful effort blocked from close range - then as the ball was immediately crossed back into the six-yard box, Palmer saw his low effort cleared off the line by Mee.
That was the last opportunity of the game as the Bees completed the double over City, though the most important result for the Blues was no injuries seemed to be sustained.
Not the way we would have wanted to end a magnificent league campaign - or our 1000th Premier League game - but there are bigger challenges ahead for City in the coming weeks.
What it means...
Not a great deal, in truth.
City's long unbeaten run of 25 games is over, but there was only pride at stake in reality for the Blues.
Arsenal's 5-0 win over Wolves means City have won the title by five points with +16 goal difference in our favour.
Next up is the FA Cup final against Manchester United at Wembley on Saturday 3 June with a 15:00 (UK) kick-off.
The Blues will enjoy a week's training at the CFA in preparation for the derby in the capital.
Then focus will shift to the Champions League against Inter in Istanbul a week later
"Congratulations to Brentford for the victory. It was a tight game.
"They pushed more and it was difficult to face them. How quick they play, how aggressive and fast in all departments.
"But I don’t have any complaints, how good we behaved, and all the players were there. I said to the players after the game, today we finished the Premier League and that you deservedly won.
"Enjoy two days with your families, don’t see each other and on Wednesday we’ll prepare the first final."
Brentford:: Raya, Hickey, Pinnock, Mee, Zanka, Henry, Onyeka (Baptiste 81), Janelt, Damsgaard, (Schade 70) Mbeumo (Ghoddos 89), Wissa (Roerslev)
Subs: Strakosha, Dasilva, Ajer, Stevens, Trevitt
Stats and facts
The Manchester City midfielder claimed the prize after again contributing the most assists in the Premier League.
De Bruyne contributed 16 assists this season to help City claim the Premier League title for a third season in a row and fifth time in six years.
The Norwegian hit a record breaking 36 goals this season, finishing six ahead of Tottenham Hotspur’s Harry Kane.
He becomes City’s third winner in the history of the Premier League after Sergio Aguero’s 26-goal haul in 2014/15 and Carlos Tevez’s 20 in 2010/11 that saw him share the award with Dimitar Berbatov.
Congratulations to both on a wonderful Premier League campaign.