Neither side were able to break the deadlock during what was a tight first half, but following the restart the O's looked the better side and McAnuff's fantastic 25-yard effort on the 53rd minute settling the tie at Fratton Park.
In response to last weekend’s defeat at home to Cambridge, O’s player-manager Kevin Nolan made four changes – including handing himself a first start.
Nicky Hunt and Shaun Brisley also came into the defence for their debuts, while Sammy returned to make his first appearance since November.
The O’s edged a five-goal thriller when the sides met on Boxing Day, but it was Portsmouth who created the first chance of the match when Marc McNulty took aim from the edge of the area inside the opening minute, though Orient stopper Alex Cisak held comfortably.
A fairly slow start to the game saw the visitors’ line-up in a 4-1-4-1 formation with Jack Payne guarding the back four, and it was fellow midfielder Sammy Moore who nearly benefitted from a slice of luck when his deflected cross dropped onto the roof of the net on the seventh minute.
With both keepers having little to do during the opening exchanges Pompey defender Keiron Freeman then ambitiously tried his luck from distance but his effort from over 35 yards flew over the bar.
With 30 minutes on the clock McNulty was presented with the greatest chance of the half when rolled through by Kyle Bennet, but the forward was superbly denied by Cisak who came rushing off his line.
Calaum Jahraldo-Martin extended his loan from Hull City until the end of the season on deadline day, and the winger found space just outside the Pompey penalty area moments later but sliced his effort wide.
Jobi McAnuff was winning several free-kicks for the O’s down the right side, and having been brought down the midfielder delivered a teasing ball into the box ten minutes before half time which Mathieu Baudry headed into the side netting.
With half time looming Bennett came close for the hosts by drilling a shot narrowly over the bar, but the final chance of the half was to drop to the O’s in stoppage time when McAnuff’s brilliant cross from the far side was headed just wide of the post by Moore.
Following the break both sides remained unchanged for the second half, and a blistering start from the O’s could have led to an opening goal but Christian Burgess managed to excellently head McAnuff’s cross away from Nolan who was lurking six yards out.
Four minutes later Nolan was then presented with a glorious opportunity to open the scoring on the 49th minute when Jack Payne’s shot was deflected into his his path, but despite lifting his shot over Fulton the ball bounced off the top of the crossbar before going out.
The O’s were looking much more threatening following the restart, and with 53 minutes on the clock took the lead in spectacular fashion when Jobi McAnuff curled a beautiful first-time shot into the top corner from 25-yards in front of the 1,031 travelling supporters.
Following McAnuff’s wonderful opener it could have been two immediately after, but Baudry could only head wide from a corner as the hosts looked shell-shocked.
With just under 25 minutes left to play it really should have been two-nil to the O’s, when a series of chances saw Jahraldo-Martin and Nicky Hunt denied, before a Nolan header was tipped out to Simpson who while leaning back could only fire over.
Three minutes later Simpson was prevented with another wonderful chance when he got on the end of McAnuff’s teasing cross, but the strikers diving header was well saved by Fulton.
Bradley Pritchard was then brought on in place of player-maanger Nolan for the final 20 minutes, and moments later Sean Clohessy came on for Moore to take up a position on the right of midfield.
Despite Portsmouth looking to try and work a way back into the game, the O's defence remained solid at the back, and with 10 minutes left to play the visitors' made their final substitution as Armand Gnanduillet replaced Simpson in attack.
With five minutes left to play Frazer Shaw produced a brilliant piece of defending from a Gary Roberts corner to head the ball away from Conor Chaplin and behind for another corner which was eventually cleared.
Gnanduillet then looked to have sealed the victory on the 88th minute following great link-up play with fellow sub Clohessy, but despite his effort beating Fulton was denied by the foot of the post.
As the match entered the last of five minutes stoppage time Hunt produced two fantastic blocks to deny Adam McGurk and then Michael Doyle as the O's held on for the victory to move back into the Play-Off places with a spectacular team performance.
PORTSMOUTH: Fulton, Freeman, Burgess, Clarke, Stevens, Close, Doyle (C), Roberts, McNulty (McGurk 73), Bennett (Chaplin 73), Smith (Evans 60)
SUBS: Bass, Davies, Webster, Barton
BOOKINGS: Stevens (40)
ORIENT: Cisak, Hunt, Baudry (C), Brisley, Shaw, Jahraldo-Martin, Payne, Moore (Clohessy 73), McAnuff, Nolan (Pritchard 70), Simpson (Gnanduillet 80)
SUBS: Sargeant, Essam, Binnom-Williams, Palmer, Gnanduillet
GOALS: McAnuff (53)
BOOKINGS: Cisak (79)
REFEREE: Graham Salisbury
ATTENDANCE: 15,643 (1,031 Orient supporters)