Holders Crystal Palace succumbed to the biggest shock in FA Cup history with a 2-1 defeat at sixth-tier Macclesfield on Saturday as Antoine Semenyo started his Manchester City career by scoring in a 10-1 rout of Exeter.
Tottenham boss Thomas Frank's future was plunged into doubt after a 2-1 home loss to Aston Villa, while Newcastle beat Bournemouth on penalties after a thrilling 3-3 draw.
In their last FA Cup outing at Wembley in May, Palace made history by beating City to win the club's first ever major trophy.
They entered the record books for the wrong reasons this time at Moss Rose as captain Paul Dawson and Isaac Buckley-Ricketts scored either side of halftime for the side managed by John Rooney, the younger brother of former England captain Wayne Rooney.
The 117 places that separate Premier League outfit Palace from Macclesfield of the National League North in the English football pyramid is the most overcome by an underdog in FA Cup history.
"I can't believe it, we never thought we would be in this position," said Rooney.
"I didn't think it was possible but there is that little bit of hope that anything can happen on the day."
Palace boss Oliver Glasner was furious at what he described as a lack of "pride" and "slapstick" defending by the Eagles, who are now winless in nine games.
"I have no explanation for what I have seen today," said the Austrian, who has been linked with the vacant managerial role at Manchester United.
Tottenham have won just three times in their last 14 games as their wait to lift the FA Cup for the first time since 1991 goes on.
Villa struck twice in a dominant first half through Emi Buendia and Morgan Rogers.
Wilson Odobert pulled a goal back early in the second half, but Spurs could not find an equaliser to force extra-time and Frank was roundly booed at the fulltime whistle.
SEMENYO SCORES
Just a day after securing his £65 million ($87 million) move from Bournemouth, Semenyo was among the scorers as City crushed League One Exeter at the Etihad.
Erling Haaland started but was remarkably not among the goals and was withdrawn at halftime.
Rico Lewis scored twice, while Max Alleyne, Rodri, Rico Lewis, Tijjani Reijnders, Nico O'Riley and Ryan McAidoo were also on target for City and Exeter netted two own goals.
Newcastle scored a 95th minute equaliser through Anthony Gordon's penalty to make it 2-2 at St. James Park after 90 minutes.
Both sides scored in extra-time as this time Bournemouth struck in stoppage time through Marcus Tavernier to force penalties.
Aaron Ramsdale saved three spot-kicks as the Magpies prevailed 7-6 in a marathon shootout.
Sunderland also needed penalties to beat Everton after a 1-1 draw.
Robin Roefs saved all three of the Toffees spot-kicks in the shootout to send the Black Cats into round four.
Premier League strugglers Wolves are now unbeaten in four games after thrashing Shrewsbury 6-1 thanks to a Jorgen Strand Larsen hat-trick.
Fulham needed three goals in the final half hour to beat Middlesbrough 3-1 at Craven Cottage, but Burnley found Championship opposition an easier proposition in thrashing Millwall 5-1.
Brentford cruised to a 2-0 win at financially stricken Sheffield Wednesday.
Liam Rosenior takes charge of Chelsea for the first time in the 2000 GMT kick-off away at Charlton.