Gassan Ahadme's deflected late goal finally broke 10-man Blackpool's brave resistance to earn Cambridge the win.
The game was in just the sixth minute when the visitors had captain George Honeyman dismissed.
Following a Blackpool corner, he was involved in an off-ball clash and received a straight red card from referee Lewis Sandoe.
The U's had first gone close after 24 minutes when Sullay Kaikai stood up a cross to Ben Knight, whose shot was kept out by goalkeeper Bailey Peacock-Farrell before Liam Bennett sent the rebound wide.
Ten minutes before half-time, Kell Watts stepped forward before hitting a fierce low effort from 20 yards, which Peacock-Farrell turned wide.
A rare Blackpool break came in the 68th minute when Albie Morgan brought Jerry Yates into play, with Jake Eastwood called on to turn his effort away.
The Seasiders stood firm and Cambridge looked to be low on ideas before Ahadme's shot took a significant deflection off Zac Ashworth to beat Peacock-Farrell nine minutes from the end.
Report supplied by PA Media
