Medy Elito's second-half hat-trick condemned Carlisle to a fourth straight defeat as Cambridge ran out 3-0 winners at Brunton Park.
The Cumbrians' automatic promotion hopes took another hit as they conceded two penalties before having James Bailey sent off in stoppage time.
Half-time substitute Elito, who had three goals in 19 U's appearances going into the game, scored both spot-kicks and secured the match ball with a strike five minutes into added time.
Carlisle looked short on confidence in a dull opening period, with Cambridge top scorer Luke Berry firing a shot over the crossbar from outside the box and George Maris going close with an effort which fizzed across the face of the Carlisle goal.
Cambridge broke the deadlock with a 66th-minute penalty after Gary Liddle fouled Berry just inside the area and Elito hammered the spot-kick high into the net.
Within five minutes, referee Robert Jones was pointing at the spot again when Nicky Adams fouled Max Clark and Elito again beat Mark Gillespie.
The home side finished with nine men after Mike Jones went off injured with all their substitutes already used before Bailey was shown a straight red card for an off the ball incident.
Elito then completed his hat-trick when he curled a shot past Gillespie from inside the area.