Having lead for over an hour, Town exited Cambridgeshire empty handed after Wes Hoolahan set one up and scored another in the final 20 minutes of a foggy afternoon at Abbey Stadium.
Jack Muldoon had put Town ahead after ten minutes with his tenth of the season, though after having much of the ball in the second half, substitute Joe Ironside levelled with 71 on the clock,
Seven minutes later and Town were down to ten men after Lloyd Kerry was shown a straight red card, with Hoolahan not wasting any time in making the numerical advantage count, finding the bottom corner in what proved to be the decisive goal.
Simon Weaver made three changes from our last completed fixture at Oldham on Boxing Day as new arrivals Josh March, Josh McPake and Mitchell Roberts were all handed their debuts.
Brendan Kiernan, Aaron Martin and Ryan Fallowfield all missed out due to being in a period of self-isolation having tested positive for Covid-19 in the most recent round of testing.
Town made an encouraging start to the afternoon, taking the lead after just ten minutes through Muldoon.
Connor Kirby had lofted a pass towards March, whose headed flick on found his new strike partner perfectly poised to beat Dimi Mitov and claim his tenth goal of the season.
Town's new strike partnership combined again five minutes later as March won possession and exchanged passes with Muldoon before striking a fraction over.
An incisive breakaway almost made it two for Town midway through the half with Muldoon, Ed Francis and George Thomson all involved, though McPake was off target when the ball broke to the debutant on the edge of the box.
Town did have their fair share of defending to do in the first half, though some excellent collective organisation and individual blocks kept the hosts out until the interval.
The hosts enjoyed a lot of the ball in the opening of the second half, but couldn't register an effort on James Belshaw's goal, until the hour mark when Paul Mullin's overhead effort was easily stopped.
Weaver then decided to freshen things up, with Jay Williams, Josh Falkingham and Lloyd Kerry replacing Roberts, Ed Francis and Kirby.
Harvey Knibbs had gone close for the hosts, but it was substitute Ironside who found the equaliser with 71 minutes played.
Wes Hoolahan had made a good run into the box before centring to Ironside who provided the deftest touch to guide the ball in off the upright.
Thirteen minutes after his introduction, Town were reduced to ten men as Kerry was shown a straight red card by Referee Carl Brook for an altercation with Harry Darling
Three minutes later and Hoolahan made the numerical advantage pay, finding the bottom corner with a clever finish from the edge of the penalty box.
That goal proved decisive with Town unable to find an equaliser, despite the best efforts of Jon Stead and William Hondermarck introduced from the bench.
Town: Belshaw, Burrell, Thomson, Lawlor, Kirby (Kerry 65), Muldoon, Hall, Francis (Falkingham 65), March (Stead 82), McPake (Hondermarck 82), Roberts (Williams 54)
Subs not used: Minter
Goals: Muldoon 10
Booked: March, Roberts, Kerry, Burrell
Sent off: Kerry
Cambridge United: Mitov, Knoyle, Digby, Taylor, Darling, Hannant, Mullin, Dunk, Hoolahan (Davies 93), May, Knibbs (Ironside 67)
Subs not used: Burton, Iredale, O'Neil, Okedina, Cundy
Goals: Ironside 71, Hoolahan 81
Booked: Darling, Mullin
Referee: C Brook