The Citizens suffered four defeats in a row across all competitions for the first time under manager Pep Guardiola before the international break, including a 2-1 EFL Cup loss away against Spurs on October 30.
A 4-1 defeat at Sporting Lisbon in the Champions League took place in between 2-1 Premier League losses to Bournemouth and Brighton & Hove Albion, and now Spurs have rubbed salt into the Citizens wounds on their own turf.
Guardiola and co made a bright start to proceedings at the Etihad Stadium, but Ange Postecoglou's men quickly weathered the storm on a drizzly evening in Manchester and fired themselves two goals in front inside the opening 20 minutes courtesy of birthday boy James Maddison.
The 28-year-old met Dejan Kulusevski's delightful cross towards the back post before cushioning a volley beyond Ederson from just a few yards out to put Spurs into the lead, and just seven minutes later he delicately chipped the Brazilian goalkeeper from close range to double his tally.
Man City were trailing by two goals at half time in a league match for the first time since their 4-2 comeback victory against none other than Spurs in January 2023, and they were tasked with replicating a similar comeback to preserve their club-record 52-game unbeaten home run lasting over two years.
Man City set unwanted losing record after Spurs hammering
However, Tottenham scored a third in the 52nd minute when Dominic Solanke teed up Pedro Porro - once on the books at Man City - to fire a first-time strike into the far corner following a free-flowing counter-attack.
Spurs rounded off a memorable victory at the Etihad with a fourth goal in second-half stoppage time when Timo Werner burst down the left channel and fizzed a low cross to the back post for fellow substitute Brennan Johnson to slide the ball home, condemning a defensively frail Citizens outfit to another disappointing loss.
Defeat for Man City represents their third in a row in the Premier League, while they have now become the first reigning top-flight champions in England to lose five games in a row across all competitions since Chelsea back in March 1956.
Man City's latest loss is also the first time that Guardiola has suffered defeat in a Premier League home match by four or more goals as Man City manager.
Under Guardiola, Man City have lost more Premier League games (seven) and have conceded more Premier League goals (26) against Spurs than they have against any other opponent.
Man City remain second in the Premier League table and five points behind leaders Liverpool, but defeat at home to Spurs come as a major blow in their quest to retain the title, as they could find themselves eight points adrift of the Merseysiders if they beat basement club Southampton on Sunday.
Guardiola, who penned a new two-year contract extension at Man City last Thursday, will hope to turn his team's fortunes around when they face Feyenoord in the Champions League next Tuesday, before travelling to Anfield to take on Liverpool in a top-of-the-table Premier League showdown five days later.