Omer Riza's double strike helped last season's beaten LDV finalists complete a Northants double in this competition.
Cambridge had beaten Rushden & Diamonds in the first round but looked to be heading out when they fell 2-0 down to headed goals by Chris Hargreaves and Marco Gabbiadini.
The game swung after the sending-off of home goalkeeper Nathan Abbey in the 31st minute, for bringing down Tom Youngs.
Although Paul Wanless saw his penalty hit the crossbar, Cambridge stormed back with three goals in a 13-minute spell eitheir side of the break.
After Daryl Burgess had headed past his own goalkeeper, Riza struck with two crisp right-foot shots to edge Cambridge in front.
Youngs sealed the victory with 19 minutes left when Lee Harper failed to hold a Luke Guttridge cross
NTFConline Man of the Match
Marco Gabbiadini - Good performance but unluckily sacrificed when Abbey was sent off.
Ref Watch
Mark Cooper was awful in the second half. He can't blamed for Town's defeat, but he made mysterious decisions against both sides. The assistants were as bad, one flagging for offside everytime and the other missing the obvious. Again this was both ways.