Liverpool were stunned by Brighton and Hove Albion at Anfield as they lost for the second home Premier League game in a row, while Manchester City stretched their winning streak at Burnley.
Having seen their 68-game unbeaten home league run ended by Burnley two weeks ago, the champions again came unstuck against an improving Brighton side.
Liverpool's next opponents are leaders City, who had less trouble seeing off Burnley as they made it 13 victories in a row in all competitions - the longest such run by a Premier League side since Arsenal between March and August 2002 (also 13).
There were also victories for Leicester City, Everton and West Ham on Wednesday, overcoming Fulham, Leeds United and Aston Villa respectively.
Here is the pick of the Opta facts on a day in which history was made as all five away sides triumphed.
Burnley 0-2 Manchester City: Jesus and Sterling keep winning run going
Twenty-four hours on from Manchester United's record-equalling 9-0 win against Southampton, City regained a three-point lead at the summit with a game in hand thanks to a routine victory at Turf Moor.
Gabriel Jesus scored for the third game in a row that he has started to give City an early lead and Raheem Sterling marked his recall to the starting line-up with his 99th goal under Pep Guardiola in all competitions.
Burnley offered little in response as they failed to register a single shot on target for the second game running, making them the first Premier League side to do so since Everton in January 2018.
It meant for a quiet day for City's defenders as they kept a sixth straight shutout in the competition - their joint-longest run without conceding - in what was a 12th successive victory in games played on a Wednesday, which is a Premier League record.
Burnley will be glad to see the back of City for another season having now lost to them by an aggregate 10-0 scoreline across their three meetings in all competitions this season, the other defeat coming in the EFL Cup.
Fulham 0-2 Leicester City: Maddison inspires Foxes to another away win
Kelechi Iheanacho's first Premier League goal in 15 appearances and a second strike of the season for James Justin earned Leicester all three points at Fulham.
James Maddison set up Iheanacho and Justin to take his goal involvement to 12 - six goals and as many assists - in his last 12 outings in all competitions, with this the first occasion he has laid on more than one goal in a Premier League match.
Leicester have now collected 26 points on their travels this season, which is already their second-highest tally in a campaign after their 2015-16 title success (39 points).
As for Fulham, they have now gone 11 games without a win in the Premier League and have lost their opening four home games of a calendar year in all competitions for the first time in their English Football League history.
Leeds United 1-2 Everton: Toffees earn rare Elland Road triumph
Everton made it four consecutive away league victories for the first time since December 1985 through first-half goals from Gylfi Sigurdsson and Dominic Calvert-Lewin.
This may just be the sweetest victory of the lot during that run, given it is only their second at Elland Road in the top flight in 38 attempts - the most recent before today coming in 2002.
It is the fifth home league match Leeds have lost in 10 games this term - the last time a Marcelo Bielsa side lost more at home in the league in a single season was Athletic Bilbao in the 2012-13 LaLiga campaign.
Sigurdsson put Everton on their way with another goal assisted by Lucas Digne - the sixth he has set up in the Premier League this season, which is the most by any defender.
Only Liverpool pair Trent Alexander-Arnold and Andy Robertson (both 28) have registered more than Digne's 17 assists since the start of the 2018-19 season.
Calvert-Lewin doubled his side's tally with his ninth headed goal in the Premier League since the start of last season - only Bayern Munich striker Robert Lewandowski (12) has scored more in Europe's top five leagues over that period.
Aston Villa 1-3 West Ham: Lingard at the double on Hammers bow
Jesse Lingard marked his first appearance for West Ham since joining on loan from Manchester United with a couple of goals against Aston Villa.
The England international is only the second player for the club to achieve that two-goal debut feat after Trevor Sinclair against Everton in January 1998.
Lingard's double came after Tomas Soucek had given West Ham the lead with his eighth league goal of the season - the most of any midfielder when excluding penalties.
Ollie Watkins gave Villa temporary hope at 2-0 but the home side could not avoid a fourth defeat in their last six league matches, compared to only four losses in their opening 14.
David Moyes has plenty of reasons to be cheerful, having overseen three successive away wins in the competition for the first time since April 2014 when at Man United, with this latest victory taking West Ham to 38 points - their highest top-flight tally after 22 games since 1985-86.
Liverpool 0-1 Brighton and Hove Albion: Alzate stuns stuns toothless champions
Liverpool's home struggles continued with defeat to Brighton, who picked up a victory in this fixture for the first time in 13 meetings in all competitions - and a first at Anfield since 1982.
The Merseyside club having now lost consecutive games at Anfield in the top flight for the first time since September 2012, having gone 68 without a home loss in the Premier League.
It is four Premier League games at Anfield without a win, meanwhile, the last three of those without scoring - the first time that has happened since October 1984 - in a goalless run spanning 348 minutes and counting.
Steven Alzate was the match-winning hero for Brighton with his first Premier League goal in his 28th appearance, coming from the first shot on target of the contest.
Toothless Liverpool offered little in reply, testing opposition keeper Robert Sanchez just once as Brighton made it four top-flight clean sheets on the bounce for the first time in their history.