Heidar Helguson gave the Bluebirds a dream start by converting a second minute penalty but David Artell equalised for the Cobblers on 37 and Alex Nicholls sealed a shock win by heading home just after the restart.
League One Scunthorpe staged a stupendous comeback to knock out Championship Derby 7-6 on penalties at Pride Park after a 5-5 draw in normal time.
Nigel Clough's Rams led 3-0 and 5-3 before the Iron forced an extra half hour by scoring twice in injury time through a Connor Jennings strike and Bobby Grant's last-gasp penalty.
Gus Poyet's Brighton were also on the end of a shock defeat as they went down 3-0 to Paolo Di Canio's newly-promoted League One Swindon at the County Ground.
Paul Benson put Di Canio's men in front in the 53rd minute and a late brace from Alan Navarro sealed a fantastic victory.
Newly-promoted Charlton were another Championship side to fall as they went down 4-3 on penalties to League One Leyton Orient at The Valley.
Scott Wagstaff gave Charlton a 28th minute lead but Mathieu Baudry equalised in first-half injury time and the visitors held their nerve to win 4-3 in the shootout with Ryan Brunt firing home the decisive kick.
And Millwall also missed out on penalties to League One Crawley Town at the New Den.
Hope Akpan and Nicky Adams twice put the visitors ahead only for the Lions to haul their way back through Darren Ward and Shaun Batt respectively.
But the visitors eased through the eventual shootout 4-1 with Crawley keeper Paul Jones the hero as he saved from Darius Henderson and Jack Smith.
Bristol City were another Championship side to crash out as they were beaten 2-1 by Gillingham at Ashton Gate.
Danny Kedwell's penalty just before the break put the Gills in front and Ben Strevens looked to have sealed victory with a 54th minute strike. City substitute Marvin Elliott scored a consolation goal in injury time.
Birmingham survived an early scare against League Two Barnet at St Andrew's when Jon Nurse put the visitors in front in the 31st minute.
The Blues blazed back with a Marlon King penalty on 38 and further goals from Stephen Caldwell and Darren Ambrose, before injury-time strikes from Wade Elliott and Peter Lovenkrands made the final scoreline harsh on the Londoners.
Crystal Palace were also forced to come from behind to beat Exeter 2-1 at St James's Park.
John O'Flynn put the hosts ahead early on, but Jermaine Easter's penalty and a Kagisho Dikgacoi goal before half-time won it for the Eagles.
League Two Bristol Rovers took a surprise 26th minute lead at Ipswich through Michael Smith, but the Tractor Boys turned it round with Jason Scotland, Tommy Smith and Aaron Cresswell setting up a 3-1 win.
Burnley were yet another Championship side forced to come from behind as Chris McCann, Charlie Austin and Dean Marney cancelled out an early Chris Shuker effort in a 3-1 win at Port Vale.
There were no such problems for Leicester, who won 4-0 at Torquay with goals from Lloyd Dyer, Ben Marshall, Matthew James and Jamie Vardy, or Peterborough, who beat Southend at London Road by the same score.
Crisis club Portsmouth crashed 3-0 at Plymouth, while another newly-relegated side, Coventry, squeaked past League Two Dagenham & Redbridge with Kevin Kilbane's injury-time penalty.
League One Stevenage beat AFC Wimbledon 3-1 and Yeovil won an all-League One clash 3-0 at home to Colchester.
Abdulai Bell-Baggie scored in the last minute of extra-time to give Tranmere a 2-1 win at Chesterfield, while League Two Oxford pulled off a minor upset with a 5-3 penalty win over Bournemouth after a goalless draw.