Demba Ba enjoyed a Chelsea debut to remember as the FA Cup holders knocked out Southampton in this season's third round while Robin van Persie saved Manchester United from defeat at West Ham United.
Queens Park Rangers left it late to avoid being eliminated by West Bromwich Albion but there were comfortable wins for Tottenham Hotspur, Norwich City and Sheffield United.
Wigan Athletic will require a replay against lower league Bournemouth while Sheffield Wednesday and MK Dons, and Southend and Brentford will also have to play again in their respective ties.
Chelsea were given a slight scare in their defence of the FA Cup against Southampton but two Ba debut goals inspired a comeback from one goal down to set up an eventual 5-1 win at St Mary's.
Joe Cole also had an excellent debut in his second time around at West Ham after assisting both of his boyhood club's goals against Manchester United at Upton Park in the evening kick-off.
But Van Persie was again the visitors' hero when stepping off the bench to score an equaliser in the final minute of stoppage time in a 2-2 draw to lead to a replay.
Wigan avoided a giant-killing against Bournemouth but will also still have to go to a replay after the Premier League club were forced to battle from behind to earn a 1-1 draw.
Two first-half Clint Dempsey goals either side of one from Gareth Bale put Tottenham on a comfortable course to an eventual 3-0 victory over League One Coventry City, who could not repeat their famous 1987 cup final shock against Spurs.
Relegation-threatened Premier League club QPR may have beaten Chelsea in midweek but they were within seconds of being knocked out of the FA Cup by West Brom before Kieron Dyer's last-gasp equaliser in a 1-1 draw.
Norwich sent a weakened team to Peterborough United but still made light work of the Championship strugglers in a 3-0 win at London Road courtesy of goals from Elliott Bennett, Simeon Jackson and Robert Snodgrass.
There was no upset at Oxford United, where goals from Tony McMahon, Dave Watson and Nick Blackman gave Sheffield United a 3-0 win.
League Two Southend United battled to a 2-2 draw with League One Brentford as Barry Corr's brace for the home side set up a replay.
Sheffield Wednesday and MK Dons will also have to play again after a 0-0 draw at Hillsborough.