One of the first reasons that Custer lost the battle had to do with incorrect intelligence estimates of the enemy forces. He and his men were operating under the assumption that there were fewer than 1000 hostile Native Americans operating in the area when in fact the numbers were likely somewhere between 1500-2500.
One of the other factors had to do with the fact that Custer's force had been effectively split when he sent Reno to attack the village and both Reno's troopers and Bentee's men were unable to rejoin Custer's main group before they were crushed by the Native American forces.
Although it is impossible to know exactly what happened because of the various accounts and the fact that none of the men directly under Custer's command survived, there are also indications that the men had panicked and were not responding to orders during the onslaught by the Native Americans. Though there is some evidence that officers were able to reassert some control prior to the final stand, this confusion and lack of organization would also contribute to the loss, particularly when added to the other factors listed above.