Sunderland suffered an embarrassing FA Cup fifth-round exit against third tier strugglers Port Vale, while Championship side Southampton upset Fulham on Sunday.
Sunderland have enjoyed an impressive first season back in the Premier League, but this was a dismal defeat for Regis Le Bris's side.
Ben Waine, a boyhood fan of Sunderland's arch rivals Newcastle, capitalised on poor marking to head the 28th-minute winner, sending Port Vale into the FA Cup quarter-finals for the first time since 1954.
Jon Brady's side appear destined for relegation, but they beat second-tier Bristol City in the fourth round and produced an even more remarkable performance to make a mockery of the 56-place gap between them and Sunderland.
The giant-killing will delight their most famous fan, pop star Robbie Williams, who grew up near their Vale Park stadium in Burslem, and is now the club's president.
It was also a memorable moment for Brady, a 50-year-old Australian who replaced the sacked Darren Moore in January and has spent his managerial career in the shadows with Brackley and Northampton.
"I'm trying to let it sink in at the moment. It was tremendous from the boys, we had to suffer at times," Brady said.
"I couldn't believe we were in the last 16, I told my kids we were in the last 32 by mistake.
"It's nice to create history, isn't it!"
Le Bris said: "I don't think we were complacent. We went strong with the ambition to win, with the knowledge that it was a tough challenge. Full credit to them."
At Craven Cottage, Ross Stewart's ice-cool penalty in stoppage-time sealed Southampton's 1-0 upset win.
It was a bitter loss for Fulham manager Marco Silva, who paid the price for a selection gamble that backfired.
Silva made nine changes following a disappointing 1-0 defeat against West Ham in the Premier League earlier this week, but his switches failed to produce the desired result.
Southampton won it in the first minute of stoppage-time when Finn Azaz was fouled by Fulham defender Joachim Andersen and Stewart drilled his spot-kick past Benjamin Lecomte.
Relegated from the Premier League last season, they are through to the FA Cup quarter-finals for the first time since 2022.
Southampton's success served as a fitting tribute to the greatest day in the club's history.
Their players wore a yellow commemorative kit to mark 50 years since they wore the same shirts when Bobby Stokes sealed second tier Southampton's shock 1976 FA Cup final win against Manchester United at Wembley.
Southampton's current crop still have a way to go to emulate the achievement of Lawrie McMenemy's men.
But Tonda Eckert's side are unbeaten in 10 games in all competitions as they chase FA Cup glory and a place in the Championship play-offs.
"You see how much it means to the club," Eckert said. "You can definitely say we feel the importance of it."
Premier League strugglers Leeds beat second tier Norwich 3-0 to reach their first FA Cup quarter-final since 2003.
Leeds boss Daniel Farke twice led Norwich to promotion to the Premier League before being sacked in 2021.
Prioritising his fight to avoid relegation, Farke's decision to make nine changes paid off against his former club.
Chasing a first appearance in the final since 1973, Leeds went in front in the 32nd minute at Elland Road.
Sean Longstaff scored for the first time since September with a clinical finish from inside the area.
Gabriel Gudmundsson slotted home in the 43rd minute and Joel Piroe bagged Leeds's third in the 85th minute.
Arsenal, Chelsea, Manchester City and Liverpool booked their quarter-final places on Friday and Saturday. (AFP)
Edited by Cecil Wong
