Three first half goals from Yeovil saw Tranmere lose their unbeaten away start to the 2010-11 season.
After two early strikes from the home side, Les Parry's side were up against it and never really found their way back into the contest with Yeovil adding a third before the half hour mark.
Rovers did pull a goal back in the final minutes through Ian Thomas-Moore but it proved to be just a consolation.
There was one change to the side that started against Peterborough, with Sam Morrow making his first start in place of the injured Adam McGurk. Joss Labadie returned from injury to be named among the substitutes while youth team striker Dale Jennings was also on the bench after impressing for the reserves in midweek.
Gavin Williams fired over Joe Collister's bar from a free kick in the third minute following a handball by Max Blanchard, but the home side took the lead a few minutes later. Jermaine Grandison's clearance struck Gavin Williams on the back and bounced to Dean Bowditch whose first time volley from 30 yards gave Collister no chance of a save.
The Glovers made it 2-0 on ten minutes and gave Rovers a mountain to climb. Andrew Williams' cross from the right reached Andy Welsh and he placed his header beyond Collister and into the Tranmere net.
A cross from Craig Alcock almost set up the home side for a third on 15 minutes but Andrew Williams' header went over the bar while appeals for a penalty against Liam Darville were turned down soon after.
Rovers' first chance came on 18 minutes when Blanchard met Ryan Fraughan's corner with a powerful header but his effort went over John Sullivan's cross bar.
Just as Tranmere showed signs of getting back into the game, Yeovil struck for a third time. A free kick fell to Paul Huntingdon inside the area and he beat Collister with a low drive to the delight of the home support.
Arnaud Mendy tried his luck with a long range effort moments after the goal and his shot wasn't too far away from the target, while Welsh sent another header straight at Collister on 33 minutes.
Labadie came on for Blanchard on 35 minutes as Les Parry tried to change things for Rovers, but the midfielder had barely been on the pitch for 30 seconds when Collister was forced into a decent save from Gavin Williams.
The move to 4-4-2 with Fraughan and Thomas-Moore on the wings almost brought a reward for Tranmere when the former found Morrow with a cross but the Northern Irish striker put his effort wide of the target.
Bowditch shot high over Collister's bar in the first minute of the second half while Morrow headed on to the roof of the Yeovil net soon after.
Lucas Akins came on for Morrow on 54 minutes and the young immediately took up position on the right wing with Thomas-Moore moving alongside Showunmi up front.
Alcock sent a header wide of Collister's goal on 58 minutes and a couple of minutes later Fraughan was replaced by Zoumana Bakayogo, with the Frenchman lining up at left back and Aaron Cresswell pushing forward to left wing.
A Cresswell free kick deflected behind for a corner on 65 minutes and Yeovil's Jean Paul Kalala shot over Collister's bar two minutes later.
Thomas-Moore volleyed wide on 77 minutes while the home side had the ball in the net for a fourth time soon after but Adam Virgo's effort was ruled out for a foul.
Akins missed with a long range shot on 80 minutes and Enoch Showunmi brought a save out of Sullivan a few minutes later.
Yeovil substitute Luke Freeman chipped over Collister but missed the target and moments later Rovers were awarded a penalty when Akins was brought down by Welsh. Thomas-Moore took the spot kick and kept up his excellent record by sending Sullivan the wrong way to make the score 3-1
Despite four minutes of time being added on, the closest Tranmere came to adding a second was a shot from Goodison that was blocked by a home defender.
Yeovil: Sullivan, Alcock, Huntingdon, Virgo, Smith, Andrew Williams (Freeman 84), Kalala, Welsh (Tudur Jones 90+3), Gavin Williams, Bowditch (Ayling 90+5). Substitutes not used: Roberts, Upson, Calver, Stam.
Tranmere: Collister, Darville, Grandison, Goodison, Cresswell, Fraughan (Bakayogo 60), Blanchard (Labadie 35), Mendy, Morrow (Akins 54), Showunmi, Thomas-Moore. Substitutes not used: Coughlin, Cathalina, Wood, Jennings.
Referee: Roger East
Yellow cards: Mendy (34), Labadie (57), Thomas-Moore (57)