Middlesbrough pulled off the shock of the round as they produced a gutsy display to knock out Manchester United 3-1 on penalties at Old Trafford.
After a goalless 120 minutes, Grant Leadbitter converted the first kick from 12 yards to get the Championship side off to the best possible start.
Captain Wayne Rooney then saw his spot kick saved by Tomás Mejías, before David Nugent let the hosts back into it as he failed to hit the target.
Andreas Pereira scored to make it 1-1, but conversions from Stewart Downing and Ben Gibson alongside misses from Michael Carrick and Ashley Young saw Aitor Karanka’s men advance to the quarter-finals.
On Tuesday, Sheffield Wednesday stunned Arsenal as they thrashed the Gunners 3-0 at Hillsborough.
The visitors made six changes from the side which beat Everton at the weekend and they were made to pay by an Owls side now unbeaten in nine matches.
Goals from Ross Wallace, Lucas Joao and Sam Hutchinson condemned Arsene Wenger’s side, who suffered injuries to Theo Walcott and Alex Oxlade-Chamberlain, to a last-16 exit.
Chelsea’s poor start to the season continues as the holders were knocked out by Stoke City 5-4 on penalties.
The Blues put in one of their better performances of the season but it took Loic Remy’s 90th minute equaliser – after Jonathan Walters had given the hosts a second half lead – to take matters into extra-time.
And after the first nine spot kicks were converted, last season’s PFA Player of the Year Eden Hazard saw his crucial effort saved by Jack Butland.
At Anfield, record eight-time winners Liverpool recorded their first victory under the leadership of Jurgen Klopp with a slender 1-0 win over Bournemouth.
The German made nine changes from Sunday’s draw against Southampton and it was one of the two which weren’t rested who got on the scoresheet as Nathaniel Clyne opened his account for the Reds.
Manchester City went goal crazy at the Etihad once more as they crushed Crystal Palace 5-1.
Strikes from Wilfried Bony, Kevin De Bruyne, Kelechi Iheanacho, Yaya Toure (pen) and Garcia Alonso means Manuel Pellegrini’s side have hit the back of the net 18 times in their last four home matches in all competitions.
Damien Delaney grabbed a consolation for the Eagles when the score was at 4-0, but the South London side won’t match their semi-final appearance of 2012.
Southampton reached the last-eight for the second consecutive season as they defeated managerless five-time winners Aston Villa 2-1 at St Mary’s.
Goals from Maya Yoshida and Graziano Pelle have the Saints eyeing a spot in the semi-finals for the first time since 1987.
Scott Sinclair’s injury-time penalty proved just a consolation for Villa, who sit bottom of the Premier League and Kevin MacDonald in temporary charge following the sacking of Tim Sherwood on Sunday.
In-form Leicester City were another club to suffer a defeat to a lower league side as they were knocked out by Hull City on penalties.
After a goalless 90 minutes, the game burst in to life when Riyad Mahrez’s 100th minute opener was cancelled out by Abel Hernandez’s strike six minutes later.
This saw the match go to spot kicks, where nine of the 10 converted; Mahrez the unlucky one who saw his effort saved by Eldin Jakupovic to see the Tigers advance to the last-eight for the first time.
At Goodison Park, Everton – finalists in 1977 and 1984 – scraped through to the quarter-finals by defeating fellow Premier League side Norwich City 4-3 on penalties.
Leon Osman cancelled out Sebastien Bassong’s opener for the Canaries, and Nathan Redmond missed the decisive spot kick after Joel Robles had previously kept out Wes Hoolahan’s effort.
Player of the Round: Kelechi Iheanacho (Manchester City)
Team of the Round: Middlesbrough
Goal of the Round: Jon Walters (Stoke City)
Middlesbrough vs Everton
Southampton vs Liverpool
Manchester City vs Hull
Stoke City vs Sheffield Wednesday