Exeter's League One play-off hopes faded as Tranmere took the three points they needed to ensure safety in style.
Just before the break Michael Kay beat Artur Krysiak with a superb left foot strike from 25 yards.
A Lucas Akins lob doubled Tranmere's lead midway through the second half and Dale Jennings set up Enoch Showunmi for the third goal five minutes later.
City had no answer and Akins scored his second with a last-minute header from a cross by substitute Adam McGurk.
Tranmere manager Les Parry tells BBC Radio Merseyside:
"I said to the lads at half time I was disappointed that we came in only 1-0 up and I think we deserved to come in with a greater gap.
"But that's football, you just have to take what you can and I knew if we carried on playing that way there would be other goals in it.
"I thought Enoch Showunmi gave a performance that has been waiting to come out for a few weeks, so it was nice to see him play that well."
Exeter City manager Paul Tisdale told BBC Radio Devon:
"We were well beaten and the winning team deserved it, there's no doubt about it.
"It's not today's fault that we find ourselves just out of the play-offs, we've had other games this year that it's more appropriate to pick fault at.
"I'm very proud of the way the players have played this year and how many results we've gained and where we sit in the table, we've come on a lot from last year."