Blackburn Rovers, Burnley, Hull City, Bolton Wanderers and Birmingham City all overcame League One opposition as Leeds United knocked out Watford.
Violence outside of Upton Park was the precursor to West Ham's 3-1 victory over Millwall, which also saw fans invade the pitch and briefly lead to play being suspended.
Neil Harris appeared to have set Millwall on the way to a surprise win before Junior Stanislas equalised three minutes from time - a goal which saw Hammers fans pour onto the pitch.
Stanislas' penalty and Zavon Hines' goal secured the win in extra time as more home supporters flooded the field at the final whistle.
Wolves needed penalties to knock out Swindon after a 0-0 draw at Molineux, with Mick McCarthy's side winning 6-5 in the shoot-out.
Port Vale stunned Sheffield Wednesday to move into the third round as the League Two side claimed an impressive 2-0 success at Vale Park.
The Owls had Francis Jeffers sent off in the first half and Vale capitalised to score two goals in the space of two minutes in the second period through Kris Taylor and Robert Taylor.
Steven Fletcher's first goals for Burnley ensured last season's Carling Cup giant-killers were not the victims of an upset after a 2-1 success at Hartlepool United.
Adam Boyd put the League One outfit in front on 39 minutes, but Fletcher equalised six minutes from the end and then hit the winner in the second half of extra time.
Birmingham City were forced to come from behind to avoid an upset after securing a 2-1 success at Southampton.
The League One club edged ahead through Adam Lallana on 51 minutes, but Lee Bowyer levelled on 77 minutes and Lee Carsley grabbed the winner for the Blues three minutes later.
Tom Cairney marked his Hull City debut with the opening goal as Phil Brown's side beat Southend United 3-1 at the KC Stadium.
Jozy Altidore also got off the mark for the Tigers and Geovanni made sure of the Premier League's club progress after Franck Moussa had pulled one back for Southend.
Blackburn also overcame League One opposition 3-1 as Sam Allardyce's men beat Gillingham at Priestfield.
David Dunn's first goal for a year set Rovers on their way before David Hoilett and Morten Gamst Pedersen scored either side of Simeon Jackson's penalty.
Mark Davies' first goal for Bolton Wanderers was enough to earn the 2004 runners-up a 1-0 victory at 2000 finalists Tranmere Rovers.
Portsmouth injected some much-needed impetus into their season as the troubled Premier League club beat Hereford United 4-1 at Fratton Park.
Frederic Piquionne's first goal for Pompey broke the deadlock and John Utaka, Niko Kranjcar and Richard Hughes were also on target before Tristan Plummer scored a consolation from the penalty spot.
Leeds United caused a minor upset as Robert Snodgrass' double earned the League One club a 2-1 home win over Watford after extra time.
Nottingham Forest came from behind to beat Middlesbrough 2-1 at the City Ground with Radoslaw Majewski netting the winner in the first half of extra time.
George Boyd struck a second-half winner as Peterborough United picked up a 2-1 win at home to Ipswich Town, who saw Tamas Priskin miss a penalty after he had earlier put the visitors ahead.
Chris Brown netted a goal in each half as Preston North End battled back from a goal down to see off Championship rivals Leicester City 2-1 at Deepdale.
Daniel Bogdanovic tucked away an injury-time penalty as the striker's brace earned Barnsley a 2-1 win at Reading.
Swansea City finished their second-round tie with eight men as Gary Hooper's penalty in extra time clinched a 2-1 win for Scunthorpe United at the Liberty Stadium.
Queens Park Rangers hung on to beat Accrington Stanley 2-1 at Loftus Road, with Wayne Routledge's injury-time goal proving decisive.