Shortly after graduating from Hogwarts, Remus joined the Order of the Phoenix along with Sirius, James, Peter, and Lily Evans, standing up against Lord Voldemort and his Death Eaters. Remus failed to find employment following his education because of his affliction as a werewolf. However, James used his wealth to financially support him.

By the height of the war, Remus' friend Sirius Black had come to distrust him, suspecting that he might be a spy for the other side. Thus, when a prophecy was made about a child who would have the power to defeat the Dark Lord, and Dumbledore identified infant Harry Potter as a possible target, Remus was not included in the plan to keep the Potters safe, though he was aware that they used the Fidelius Charm. James and Lily Potter wanted to use Sirius as their Secret-Keeper, but Sirius thought that would be too obvious, and thus suggested Peter Pettigrew instead, who would be a nearly unpredictable move, him being known for his "measly empty-headedness." Neither Dumbledore or Lupin knew of this switch.

At the time of Lily and James' death, Lupin was in the north of the country on Order of the Phoenix business when he discovered what had, apparently, happened. This was one of the most traumatic events of Remus' life, especially since, within the next day, he would also be losing his other two best friends. Sirius was imprisoned in Azkaban for supposedly murdering Pettigrew and twelve Muggles with one curse