Bottom of the Premier League and seemingly destined for relegation, Southampton got no respite in the FA Cup as second tier Burnley won 1-0 at St Mary's.
Scott Parker's team went in front after 77 minutes when Marcus Edwards scored from close-range on his debut after signing on loan from Sporting Lisbon.
Edwards, 26, was once compared to Lionel Messi before being released by Tottenham and rebuilding his career in Lisbon.
It is almost 600 minutes since Championship promotion chasers Burnley last conceded a goal, with 10 clean-sheets in their last 11 games.
The last FA Cup tie at Goodison Park ended in disappointment for Everton, who are moving to a new stadium next season, as Bournemouth cruised to a 2-0 victory.
Andoni Iraola's side went ahead when Everton captain James Tarkowski fouled Antoine Semenyo in the area and the Bournemouth winger picked himself up to convert the 23rd minute penalty.
Dan Jebbison tapped in Bournemouth's second on the rebound after Marcus Tavernier's shot was parried by Jordan Pickford in the 42nd minute.
Rodrigo Muniz scored twice as Fulham won 2-1 at third tier Wigan.
Muniz bundled home Ryan Sessegnon's cross in the 23rd minute before Jonny Smith's curler hauled Wigan level after 50 minutes.
Fulham were back in front five minutes later when Muniz slotted home from Andreas Pereira's pass.
Ipswich, second bottom of the Premier League, swept to a 4-1 win against Frank Lampard's Coventry.
George Hirst's second minute penalty was quickly cancelled by out Joel Latibeaudiere's eighth minute equaliser for the second tier hosts.
But Jack Clarke restored Ipswich's lead in the 28th minute and struck again after 37 minutes before Jaden Philogene's 63rd minute effort sealed the rout.
Millwall reached the fifth round for the first time since 2018-19 thanks to Femi Azeez's double in a 2-0 win at Championship leaders Leeds.
Leeds boss Daniel Farke made 10 changes and paid the price as Azeez opened the scoring with a deflected effort from the edge of the area in the 30th minute.
Azeez netted again for the 2004 FA Cup finalists with a fierce drive in the 55th minute before Millwall keeper Liam Roberts saved Pascal Struijk's penalty.
Later on Saturday, Chelsea travel to Brighton and Newcastle visit third tier Birmingham.