Fleetwood Town cruised past last season's Johnstone's Paint Trophy winners Crewe Alexandra with a flurry of goals either side of half time at Highbury.
David Ball and Jon Parkin both scored before the break for the home side, while Nathan Pond extended their advantage at the start of the second, before Matty Blair rounded off the win in stoppage time.
Trophy favourites Wolverhampton Wanderers were knocked out in a penalty shootout by Notts County.
The visitors had the majority of the chances before full time and misses from Bjorn Sigurdarson, Kevin Foley and James Henry handed County the win.
Newport County overturned a 2-0 deficit against Crawley Town to secure their place in the next round.
Early goals from Emile Sinclair and Mike Jones gave the hosts the lead, but a Chris Zebroski effort kept the League Two side in contention.
James Hurst was sent off early in the second half, allowing Adam Chapman to level from the spot, before an own goal from Connor Essam handed the Welsh side the victory.
There were six goals in 15 minutes during Dagenham & Redbridge's 5-2 win over Southend United.
A quick-fire brace from Cauley Woodrow put the home team ahead, cancelling out Zavon Hines's first-half effort.
However, three goals in eight minutes from Hines, Brian Saah and Chris Dickson saw the Daggers regain the lead.
League Two's Hartlepool United stunned Sheffield United to claim a place in the next round.
James Poole struck the ball home for the visitors towards the end of the first half, while Jose Baxter spurned several chances for the Blades in the second period.
Portsmouth survived a strong finish from Oxford United to keep themselves in contention for the trophy.
Yassin Moutaouakil and Patrick Agyemang put Pompey ahead, while a late goal from James Constable gave Oxford hope, but they were unable to draw level.
Leyton Orient needed penalties to get past Coventry City after a goalless 90 minutes.
The home side won the shootout 4-2, with Franck Moussa and John Fleck both missing for the visitors, before Lloyd James converted the decisive spot kick.
Oldham Athletic scored twice inside the opening 10 minutes to beat in-form Preston North End.
Danny Philliskirk broke the deadlock after just two minutes, before a ninth-minute effort from James Wesolowski
Peterborough United held on to ensure their place in the third round with a 2-1 win over Brentford.
An own goal from Martin Taylor and a Grant McCann penalty helped the hosts to a two-goal lead, but Ben Nugent kept the visitors in contention with a goal inside the final 10 minutes. However, his teammates were unable to find an equaliser.
Swindon Town came from behind to beat Plymouth Argyle 2-1. Andre Blackman put the visitors ahead after just seven minutes, but Jack Barthram ensured that Swindon were level at half time, before Nick Ajose's winner early in the second half.
Stevenage scored twice in the second half to overturn a first-half deficit against MK Dons.
Shaun Williams converted from the spot after 25 minutes to give the visitors the lead at half time, but Francois Zoko and Filipe Morais helped the hosts to edge ahead after the break.
Rotherham United secured a comfortable victory at Bootham Crescent, beating York City 3-0. An own goal from Chris Smith gave the visitors the lead, before second-half efforts from Kieran Agard and Alex Revell ensured that the Millers eased into the next round.
Carlisle United edged past Morecambe on penalties in a closely-fought tie at the Globe Arena. After a goalless 90 minutes, both sides made a strong start to the shootout, but a couple of misses by the hosts ensured that Carlisle progress.
A strong first-half performance ensured that Wycombe Wanderers overcame higher-league opponents Bristol City.
Matt Bloomfield and Billy Knott gave the hosts a two-goal lead at half time before Brendan Moloney got one back for the visitors, but it was not enough to stop one of the tournament's favourites from being knocked out.
Gary McSheffrey scored inside the final 20 minutes to see Chesterfield past Mansfield Town this evening. Martin Riley had a good chance for an equaliser late on for the home side, but Tommy Lee was able to parry the ball away.
A first-half strike from Joe Rafferty was enough for Rochdale to move past Port Vale. The visitors took the lead just before half time, while Port Vale had few chances to get back on level terms in the second half.
Results in full: Crawley Town 2-3 Newport County, Port Vale 0-1 Rochdale, Leyton Orient 0-0 (4-2 on penalties) Coventry City, Peterborough United 2-1 Brentford, Fleetwood Town 4-0 Crewe Alexandra, Morecambe 0-0 (3-4 on penalties) Carlisle United, Preston North End 0-2 Oldham, York City 0-3 Rotherham, Sheffield United 0-1 Hartlepool United, Wolverhampton Wanderers 0-0 (1-3 on penalties) Notts County, Mansfield Town 0-1 Chesterfield, Oxford United 1-2 Portsmouth, Swindon Town 2-1 Plymouth Argyle, Wycombe Wanderers 2-1 Bristol City, Southend United 2-5 Dagenham & Redbridge, Stevenage 2-1 MK Dons
