Ten man Rovers lost only their third home game of 2012-13 as Carlisle left Prenton Park with all three points.
The sending off of Jean-Louis Akpa Akpro before half time cost Tranmere dearly, with the visitors scoring soon after and holding on for the win.
Ronnie Moore went with an unchanged team following the win over Brentford, with Jean-Louis Akpa Akpro and David Amoo starting up front together.
The first shot of the game came on five minutes but Paul Thirlwell's volleyed effort for the visitors from 25 yards went high over Owain Fon Williams' bar.
A lay off from Amoo gave Andy Robinson a shooting opportunity from 25 yards on six minutes but the Rovers captain couldn't keep his attempt down and Mark Gillespie was untroubled in the Carlisle goal.
Gillespie did well to deal with a dipping Adam McGurk cross on 13 minutes, with the keeper catching the ball underneath his cross bar despite colliding with the goalpost.
Max Power sent a 20 yard shot over the bar on 16 minutes while Carlisle's JP McGovern hit the near post direct from a corner four minutes later, with Rovers quickly clearning.
Andy Welsh broke into the left side of the Tranmere area on 27 minutes and tried to pick out Lee Miller in the six yard box but his cross was well cut out by Donervorn Daniels and Fon Williams.
The chance for the visitors seemed to spark Rovers into life, with Amoo running on to a long ball and getting one on one with Gillespie only to see the keeper save a low shot with his feet, while McGurk headed wide at the back post soon after from a Zoumana Bakayogo cross.
Amoo hooked a right foot shot wide after Ash Taylor headed Robinson's free kick back across goal on 35 minutes but soon after Rovers were reduced to ten men when Akpa Akpro was shown a straight red card for kicking out at Frank Simek following a tussle for the ball on the left wing.
The visitors took advantage of the extra man two minutes before half time. Rovers cleared a corner but had nobody forward to hold up play. The ball was played back into the Tranmere area and eventually landed at the feet of Rory Loy who shot across Fon Williams and into the net, beating the attempt of Bakayogo to clear off the line.
McGurk came close to equalising five minutes into the second half when he headed Bakayogo's cross towards the near post but Gillespie pulled off a fine one handed save to tip the ball around the post.
Play swung from end to end with Rovers urged forward by the home crowd only for Carlisle to respond with a series of set pieces around the Tranmere area.
Cole Stockton replaced Amoo just past the hour mark and moments later Rovers it needed a goal line clearance from Matty Robson to keep out Taylor's header from a set piece.
Liam Palmer's dipping 30 yard shot was parried by Gillespie on 64 minutes and Robinson shot across goal and wide soon after from the edge of the area.
Stockton latched on to McGurk's flick on with 20 minutes remaining and side stepped one defender to get into the area before moving wide of goal to get past another. However, his right foot shot was deflected wide of the target.
Palmer thought he had finally scored his first goal for the Club on 72 minutes when he turned a Robinson free kick against the post and followed up by firing in on the goal line but as he ran away to celebrate the assistant referee raised his flag for offside.
Stockton sent a close range header over the bar on 74 minutes and he was joined up front by Michael O'Halloran two minutes later, with the Bolton Wanderers loanee replacing McGurk.
Two more Stockton efforts were charged down on 90 minutes while Bakayogo's header deep in injury time from Holmes' cross was well saved by Gillespie.
Tranmere: Fon Williams, Holmes, Taylor, Daniels, Bakayogo, McGurk (O'Halloran 76), Palmer, Power (Bell-Baggie 85), Robinson, Amoo (Stockton 62), Akpa Akpro. Substitutes: Mooney, Goodison, Black, Harrison.
Carlisle: Gillespie, Simek, Robson, McGovern, Livesey, Welsh (Noble 74), Loy (Symington 86), Thirlwell, Miller, Berrett, O'Hanlon. Substitutes: Collin, Murphy, Edwards, Potts, Beck.
Referee: Tony Harrington
Yellow cards: Holmes (67)
Red card: Akpa Akpro (36)