Manchester United shattered Manchester City's record winning streak with an impressive 2-0 victory against the Premier League leaders, while Liverpool hit a new low as relegation-threatened Fulham won at Anfield on Sunday.
Pep Guardiola's side were on an English top-flight record run of 21 successive wins in all competitions heading into the Manchester derby.
But United ruined City's 28-game unbeaten run in all competitions thanks to an early penalty from Bruno Fernandes and Luke Shaw's second-half strike at the Etihad Stadium.
Ole Gunnar Solskjaer's team, unbeaten in their last 22 away league games, moved above Leicester into second place, but they are still 11 points behind City with 10 games left.
Despite surrendering their 15-match winning league run in their first defeat since losing at Tottenham in November, City remain firm favourites to lift the title for the third time in four seasons.
"We will be the news because we lost. But the news is 21 victories in a row. We played much better than the game against West Ham which we won," Guardiola said.
"We will try to win as many games as possible to be champions."
Barring a dramatic collapse from City in the closing weeks, United's third win in the last four league meetings with their bitter rivals is likely to be remembered for cementing a top-four place rather than rekindling their title hopes.
"When you come away with a 2-0 win and another clean sheet and a performance like this then you are delighted," Solskjaer said. "But City are too far ahead to think we can catch them."
With just 34 seconds gone, Anthony Martial made a dangerous raid into the City area and Gabriel Jesus responded with a needless, clumsy challenge that sent the French striker sprawling.
Fernandes stepped up to take the penalty and squeezed his shot past Ederson, who got a hand on the ball but couldn't keep it out.
It was United's first goal in four games, putting City were behind for the first time in 20 league games.
In the 50th minute, Shaw broke from deep inside his own half, played a one-two with Marcus Rashford and fired a fine finish past Ederson from just inside the area.
Likely to be replaced by City as champions, Liverpool have now lost six consecutive home league games after third-bottom Fulham's well-deserved 1-0 win.
That dismal run is all the more remarkable as Jurgen Klopp's men had gone nearly four years without a league defeat at home in 68 games between April 2017 and January this year.
Liverpool's best chance of qualifying for next season's Champions League may now be in winning the European Cup as they sit eighth, four points adrift of the top four, having played at least one game more than all their rivals.
Mohamed Salah was at fault for the only goal in first-half stoppage time.
Mario Lemina outmuscled Salah to win the ball inside the Liverpool box before firing low across Alisson Becker into the far corner.
"We don't have the mentality we are used to but the boys want to win games and I saw that today. We still made mistakes and that's the problem," Klopp said.
Tottenham are back in the hunt for a top-four berth after Gareth Bale and Harry Kane scored twice in a 4-1 rout of Crystal Palace.
The revitalised Bale tapped in from Kane's cross in the 25th minute before Christian Benteke headed Palace's equaliser in first half stoppage-time.
Bale restored Tottenham's advantage in the 49th minute when the on-loan Real Madrid forward headed home for his sixth goal in his last six games.
Kane's brilliant 20-yard rocket made it three in the 52nd minute and the Tottenham striker netted again from Son Heung-min's pass in the 77th minute.
It was the 14th goal Kane and Son had been directly involved in this term, beating the previous Premier League record set by Alan Shearer and Chris Sutton for Blackburn in the 1994-95 season.
Sixth-placed Tottenham are two points behind Chelsea after their third successive win.
Newcastle are just one point above the relegation zone after a 0-0 draw at second-bottom West Brom.
COMMENTS
Comments are moderated and generally will be posted if they are on-topic and not abusive.
For more information, please see our Comments FAQ