A brace from James Maddison fired the visitors into a comfortable first half lead at the Etihad Stadium.
It piled the misery on the Premier League champions, who had already lost their last four matches in all competitions.
Of those defeats, one came against Spurs in the Carabao Cup last month.
They have also been beaten by Bournemouth, Sporting and Brighton
Despite their poor form, though, Guardiola penned a new deal this week through to the summer of 2027.
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The news failed to inspire City, however, as they fell 2-0 down inside the opening quarter of the match.
Things then got worse when Pedro Porro made it 3-0 and Brennan Johnson made it four in injury time.
Those strikes meant City were handed their heaviest home league defeat under Guardiola.
The loss also ended their 52-game unbeaten run at the Etihad.
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Maddison's goals also set a record as the earliest the hosts have trailed by the scoreline in a Premier League home match since December 2010.
On that occasion, Everton raced into a two-goal lead after just 19 minutes in Manchester.
Goals from Tim Cahill and Leighton Baines that day set the Toffees on their way to a 2-1 victory.
In the 14 years since, City have won eight Premier League titles, with six coming under Guardiola.
The Spaniard has lifted 12 other trophies during his tenure, including the Champions League and Club World Cup.
However, he has so far had to settle for unwanted history this term.
His side's loss to the Seagulls a fortnight ago marked the first time in his managerial career he had lost four matches in a row.
It was also the first time in 18 years City had suffered so many consecutive defeats.
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Meanwhile, Saturday's loss also means they have lost three league matches in a row under Guardiola for the first time.
The former Bayern Munich manager had previously been beaten in three straight matches during his time in charge of the German giants.