Matt Harrold had given the O’s a 22nd minute lead when he swept home from a James Dayton cross, only for Andy Cook to equalise four minutes later.
After going into the break level it was the hosts who then secured the victory in the second half as James Norwood’s 71st minute header proved to be the difference on the night.
For the trip to Prenton Park, Head Coach Steve Davis made one change to the starting XI as he brought in Matt Harrold to replace David Mooney who dropped to the bench.
On a wet night in front of the BT Sport cameras, it was the hosts who threatened early on as Lewis Buxton’s fourth minute free-kick was deflected wide for a corner before Jeff Hughes dragged a shot wide from distance soon after.
Tranmere then felt they should have had a penalty when O’s defender Mark Ellis tangled with James Norwood in the area, though the appeal was swiftly waved away by referee Adam Bromley.
With the game just over 20 minutes old, goalkeeper Charlie Grainger produced a wonderful save to deny the hosts as Andy Cook’s close-range effort was superbly clawed off the line.
The Orient number one’s saved proved to be vital, as seconds later Orient took a 22nd minute lead.
A swift counter saw Jobi McAnuff’s shot deflected out to the right for James Dayton, who showed great composure to drill the ball back across the box to which Matt Harrold swept home the opener.
Despite making the breakthough, the lead was not to last long as Tranmere levelled four minutes later when Cook was on hand to sweep home after Grainger had pulled off yet another fine stop to thwart Norwood.
It was an even affair throughout the first half as both sides created chances, but it was Orient who came close to restoring their lead on two occasions as first Dayton flashed a 25-yard effort wide of the post before Ellis headed wide from inside the box.
The hosts then responded with a chance of their own on the 36th minute as Connor Jennings’ half-volley fizzed wide, in what proved to be the final effort of the half as the teams went into the break all square.
Following the interval both sides returned unchanged, as the game continued in a similar fashion to the first half with both sides pushing for the third goal of the night.
It was Tranmere who had the first effort of the half, with Norburn curling a low free-kick into the side-netting before the midfielder forced Grainger into a top save just after the hour mark to parry his shot behind for a corner.
From the corner Grainger was forced into making another top save, tipping Cook’s header over the bar to which the next ball into the box caused brief panic before the whistle was blown for an O’s free-kick.
Despite withstanding the pressure Orient were forced into the first change of the night on the 65th minute as Jamie Sendles-White came on in place of Jake Caprice who limped off gingerly.
Following Caprice’s departure Sendles-White took up a position in the centre of midfield alongside Craig Clay whilst Alex Lawless reverted to right back.
Tranmere had created the more chances throughout the second half, and with 71 minutes played took the lead when Mottley-Henry burst forward down the left and clipped the ball across goal for Norwood to head in from a yard out.
Having fallen behind the O’s responded well as James Brophy combined well with McAnuff on the flank to earn a corner, though Sendles-White could only direct his header wide of the far post with 14 minutes remaining.
With just over 10 minutes remaining Head Coach Steve Davis then opted for a double substitution, introducing Romuald Boco and David Mooney for the final stages in place of Dayton and Harrold.
The substitutions also saw Orient switch to a 3-5-2 formation, though it was Tranmere who could have put the game to bed on the 82nd minute when Adam Buxton’s cross was met by Jennings at the far post who saw his header flash across goal and wide of the post.
Despite five minutes stoppage time being shown by the fourth official, Orient were unable to force an equaliser as Tranmere clinched the three points.
TRANMERE: Davies, Buxton, McNulty (C), Sutton, Ridehalgh, Tollitt (Mottley-Henry 41), Norburn (Harris 89), Hughes, Jennings, Cook, Norwood
SUBS: Wharton, Alabi, Mangan
GOALS: Cook (26), Norwood (71)
BOOKED: Norburn (32), Hughes (58), Mottley-Henry (67)
ORIENT: Grainger, Caprice (Sendles-White 65), Ellis, Happe, Brophy, Lawless (C), Clay, Dayton (Boco 79), McAnuff, Harrold (Mooney 79), Bonne
SUBS: Sargeant, Mooney
GOALS: Harrold (22)
BOOKED: Lawless (52), Mooney (81)
REFEREE: Adam Bromley
ATTENDANCE: 4,145 (157 Orient supporters)