James Maddison marked his 28th birthday with two first-half goals before Pedro Porro scored against his former club, with Brennan Johnson completing the rout.
Defeat meant the end of City's 52-game unbeaten home run and left them on a losing streak unlike anything else Guardiola has experienced since arriving in Manchester in 2016.
They also remain five points adrift of Premier League leaders Liverpool, with Arne Slot's side facing bottom club Southampton on Sunday.
City travel to Liverpool next weekend and Guardiola conceded their defence of the title is realistically over should they lose and fall 11 points behind the Reds.
The former Barcelona and Bayern Munich boss only this week signed a two-year contract extension until 2027.
But hopes that would bring the positivity needed to turn City's fortunes around proved short-lived.
"In eight years we have never lived this kind of situation," said Guardiola, whose side face Feyenoord in the Champions League on Tuesday.
"Now we have to live it and break it winning the next games, especially the next one. Now we see things in one way, maybe in a few weeks we see it differently."
After a bright start, City collapsed when Maddison opened the scoring with virtually Tottenham's first attack.
Guardiola's men have rewritten the record books of English football in recent years by winning four consecutive Premier League titles.
But he recognised that they are stuck in a negative mental spiral after a series of unexpected defeats.
"We are a bit fragile right now, that is obvious for the fact that we struggled today to score goals. And after when they arrived, they scored," he added.
"We are playing a little bit in our thoughts, with a little bit of negativity, but it's normal. Football is a sense of mood. And when you win a lot, there's continuity that gives us self-confidence that you can do it.
"When you lose three games in a row in the Premier League, that situation is always a little bit there."
City defender Kyle Walker said it was vital the team went "back to the basics and got a clean sheet".
He added: "If we concede four goals at home we have to score five. It's not just the back four, five or six -- it's all 11 players on the pitch."
Despite a 4-1 defeat to Sporting Lisbon last time out in the Champions League, City are still well-placed to reach the knockout stages.
"The best way to turn this round is on Tuesday. Hopefully the mojo comes back and we see the normal City from the past eight seasons," added Walker.
Even in their best moments, though, City have struggled away at Anfield, where they have not won in front of a crowd since 2003.
"It's a great game to turn it around and take three points from the team who sit above you," said Walker on facing Liverpool.
"But we can't put in a performance like that or we'll get walked over."
