Having lost to Liverpool just two days earlier, Sir Alex Ferguson changed his entire starting XI as Manchester United battled to a 2-0 victory over Barnsley at Oakwell.
Tykes manager Mark Robins had been hoping to mastermind a cup upset against Manchester United 19 years after scoring a famous FA Cup goal for the Red Devils that is widely credited to have saved Ferguson's job.
However, his plans were left in tatters after just six minutes when poor defending allowed Danny Welbeck to find space in the box and head home a pinpoint Anderson corner.
Michael Owen doubled United's lead with a neat run and finish on 59 minutes but Gary Neville was then shown a straight red card for a foul on Adam Hammill to leave Barnsley with a numerical advantage for the closing stages.
The Championship side created chances to reduce their arrears but failed to beat Ben Foster as United held on to book their place in the next round.
Tottenham remain in the hunt for a third straight final appearance following a 2-0 win over injury-hit Everton at White Hart Lane.
There was nothing to choose between the sides until Tom Huddlestone crashed in powerful volley on 31 minutes and the result was put beyond doubt after the interval.
Robbie Keane earned a penalty after a foul by Sylvain Distin and, although Tim Howard saved his spot-kick, the Irishman showed great determination to scramble home the rebound at about the fifth attempt.
Blackburn's preparations for their home tie with Peterborough had been disrupted by an outbreak of swine flu at Ewood Park but they proved too strong for Championship strugglers Peterborough with a thrilling 5-2 success.
Morten Gamst Pedersen curled home a magnificent free-kick on four minutes to put Rovers in control, only for Chris Whelpdale to nod in an equaliser 13 minutes later following good work from Tommy Rowe.
Posh were then reduced to ten men when goalkeeper Joe Lewis was sent off for bringing down Pedersen just before the interval and Steven Reid converted the resulting penalty despite losing his footing in the run-up.
Blackburn were surprisingly pegged back to 2-2 as George Boyd fired in a terrific effort on 50 minutes, but Michel Salgado restored their lead with his first goal for the club seven minutes later.
Benni McCarthy then gave Rovers a two-goal cushion after 72 minutes and Nikola Kalinic scored from the penalty spot after a Krystian Pearce handball.
Portsmouth may be facing a fight for Premier League survival but manager Paul Hart has been encouraged by recent performances and the long-awaited goals finally arrived at Fratton Park in a convincing 4-0 triumph against top-flight rivals Stoke.
Frederic Piquionne broke the deadlock with a header from Nadir Belhadj's left-wing cross on 17 minutes and the French striker then turned provider for Danny Webber to score early in the second half.
Piquionne grabbed his second of the evening just before the hour mark and Kanu got in on the act with nine minutes remaining to boost confidence ahead of future challenges.
In the final game of the night, Aston Villa prevailed on penalties against Sunderland following a goalless 120 minutes.
Both managers had selected strong sides for the Stadium of Light clash but it was an uninspiring contest for long periods with chances few and far between.
The Black Cats had the opportunity to win it in normal time when Carlos Cuellar was adjudged to have handled the ball inside the area, but Kenwyne Jones' weak penalty was kept out by Brad Guzan.
Guzan then saved three more spot-kicks in the shoot-out to spark Villa celebrations and condemn Sunderland to the narrowest of defeats.