They only had themselves to blame as they missed a 77th minute penalty with Carlisle skipper Kevin Gray sent off for deliberate handball.
With their regular taker on the bench Grimsby gave the task to full-back Tom Newey, but he struck his penalty too hard and the ball flew back into play off the underside of the bar.
An equaliser then, and with 13 minutes remaining against ten men, the Mariners would have fancied their chances of going on to take all three points.
But their injury-hit side faced one game too many and against a lively Carlisle side they did well to go in 1-1 at half-time.
Grimsby in fact took an early lead when midfielder Ciaran Toner scored from 25 yards after a poor punch out from the Carlisle keeper. But seven minutes later the visitors were level when Spaniard Zigor Aranalde fired in off the post.
Carlisle continued to push forward and the quick-silver Karl Hawley crashed a great shot against the bar which was a real let-off for Grimsby.
But the winning goal came from the visitors on 75 minutes. Good work down the right saw the ball come over and Aranalde squeezed in his second goal with his head much to the delight of the Carlisle fans behind that goal.
But then came the late drama and, even after missing the penalty, Grimsby swarmed forward and sub Martin Gritton headed wide from an open goal. Two minutes later sub Nick Heggarty shot against the bar for what was Grimsby's last chance.
Grimsby have a 12-day break before they face Mansfield at home on January 14 which should at least give their injuries a chance to heal.