After beating Spurs 6-0 at the Etihad Stadium, Manuel Pellegrini's side was unstoppable at White Hart Lane as well and extended its unbeaten run to 20 matches, in which time they have scored 69 goals.
City received a decisive boost when Danny Rose was sent off in the 50th minute for tripping Edin Dzeko. Yaya Toure converted the penalty before Dzeko made it 3-0. Etienne Capoue's pulled one back but Stevan Jovetic and Vincent Kompany added gloss to victory.
City now leads Arsenal by one point, with Chelsea lagging three points behind. Elsewhere, Sunderland beat Stoke 1-0 and Aston Villa defeated West Bromwich Albion 4-3 in a derby that saw six goals scored in the first half.
Since the thrashing at City and the subsequent sacking of coach Andre Villas-Boas, Tim Sherwood had overseen an upturn in fortunes at White Hart Lane, with Spurs undefeated under their new manager and having won their last four Premier League matches.
Pellegrini's team was therefore expecting a tougher test at White Hart Lane.
They had the better start as the in-form Sergio Aguero went close in the fourth minute with a shot from an angle that hit the post.
Aguero looked unstoppable during the first half and put his team in front in the 15th minute, scoring for the eighth successive game when he slipped the ball past goalkeeper Hugo Lloris from David Silva's assist.
The Argentina striker's header then forced Lloris to a beautiful one-handed save. Unfortunately for City, Aguero picked up an apparent hamstring injury while sprinting for the ball and was replaced by Stevan Jovetic.
"We will see tomorrow with the doctor what happened with him, maybe he has a problem with his hamstring, we will see how serious it is," Pellegrini said. "Sergio is a top player but we don't depend on just one player so we hope it's the moment where Stevan Jovetic can play and hope that Sergio can join us again as soon as possible."
The striker's injury was not a factor as City was awarded a penalty five minute into the second half when Rose was shown a red card for bringing down Dzeko with a tackle from behind. Toure converted by sending Lloris the wrong way.
A man down, Tottenham conceded another goal two minutes later, with Dzeko scoring from a rebound after Lloris saved Silva's effort onto the post.
Tottenham's Etienne Capoue pulled one back in the 59th from a corner, but Jovetic then found space in the area to beat Lloris and Kompany rounded off a perfect night with a clean finish.
At Stamford Bridge, West Ham defended for most of the second half and managed to contain Chelsea's assaults to secure an important point in its fight to remain in the top flight next season.
Demba Ba hit the post from close range in added time before Hazard missed two consecutive chances and Eto'o had a goal disallowed for a foul on Adrian.
"They defended with their hearts, I respect that and praise that," Mourinho said. "I don't think with matches like this we can sell Premier League across the world. My team did everything possible."
Aston Villa edged West Brom in a prolific West Midlands derby. The Baggies led 2-0 after Chris Brunt opened the scoring and Fabian Delph scored an own goal.
But Andreas Weimann lobbed in to pull one back, Leandro Bacuna levelled and Delph made amends to put Villa ahead.
Youssuf Mulumbu equalized two minutes before the break before Benteke had the final say when he earned a penalty and slotted the spot kick into the bottom left corner in the 64th.
Benteke has now scored three goals in three games, helping Villa establish itself firmly in midtable. West Brom fell to 15th, just three points outside the relegation zone.
Adam Johnson scored in the first half to give Sunderland a 1-0 win over 10-man Stoke and lift his team out of the relegation zone for the first time since August.