Two goals in ten minutes midway through the second half put Tranmere in control against dogged Oldham.
Oldham had looked the better side for the first hour but failed to take some gilt-edged chances.
The visitors were disrupted early when goalkeeper Les Pogliacomi was forced off after only 14 minutes with a groin injury.
Craig Mawson took over and had no chance with either of the home goals.
Oldham should have gone ahead in the 44th minute when Jermaine Johnson raced clear from the halfway line. But his shot past home keeper John Achterberg just cleared the left-hand post.
Then moments later Kevin Betsy had another chance from a quick breakout, but fired well over.
It needed a fine save by Achterberg to deny Johnson in the 58th minute.
Tranmere introduced Jason McAteer in place of Stephen Jennings just short of the hour and he immediately made his presence felt in midfield.
Tranmere broke the deadlock in the 65th minute. Eugene Dadi, who had replaced the injured Calvin Zola in the 32nd minute, headed home at the far post from a cross by Iain Hume.
Then Hume doubled the advantage with an exquisite shot from the corner of the box over keeper Mawson.
The Merseysiders should have had a third goal near the close. Substitute David Beresford got clear but in trying to mob Mawson put the ball over the bar.
Johnson, Betsy and Will Haining were excellent for the losers. Hume starred for the Merseysiders for whom it was a fourth successive home victory.