West Ham crashed out of the FA Cup at Wigan while Tottenham needed a late Harry Kane equaliser to avoid a shock loss at Newport.
Will Grigg was the Wigan hero of the fourth-round tie at the DW Stadium, scoring both goals as the League One side stunned the 10-man Hammers, of the Premier League, 2-0.
The Northern Ireland international opened the scoring after just seven minutes and then added the second from the penalty spot after West Ham had Arthur Masuaku sent off early in the second half following an off-the-ball incident involving Nick Powell.
There were suggestions he may have spat at the Wigan player.
Another top-flight side, Leicester, had no such concerns as they eased past their League One opponents Peterborough 5-1 at the ABAX Stadium.
New signing Fousseni Diabate and Kelechi Iheanacho both struck twice with Onyinye Ndidi also on the scoresheet.
Andrew Hughes shot through a crowded area to give Posh brief hope by making it 3-1 in the second half but it proved mere consolation.
Glenn Murray netted a late winner as Premier League Brighton snatched a 1-0 win at Championship Middlesbrough.
Boro had looked like taking the Seagulls to a replay but substitute Murray bundled home a scrappy 90th-minute clincher.
Premier League bottom side Swansea were held to a 1-1 draw by League Two promotion challengers Notts County.
Huddersfield’s clash with Birmingham also ended all square as as David Wagner’s men were held 1-1 at the John Smith’s Stadium. Steve Mounie put the Terriers ahead in the first half but Lukas Jutkiewicz levelled soon after the break.
Jack Stephens’s fourth-minute goal proved the difference as Southampton beat Watford 1-0 in their all-Premier League clash at St Mary’s, meaning Javi Gracia’s first match in charge of the Hornets ended in defeat.
Ben Thompson scored a late equaliser as Championship side Millwall avoided defeat to League One strugglers Rochdale.
Goals from Ian Henderson and Matt Done, in reply to an early Jed Wallace penalty, had put Dale on course for a shock win but Thompson had the final say in the 90th minute as it finished 2-2.
An 80th-minute penalty from Billy Sharp gave Sheffield United a 1-0 win over Preston, while Hull beat Nottingham Forest 2-1 in another all-Championship contest. First-half goals from Jarrod Bowen and Nouha Dicko proved enough for the Tigers, despite a late reply from Apostolos Vellios.