Pompey, who are currently sitting in ninth position, have seen their playoff aspirations dented by three consecutive draws.
Match preview
Prior to Saturday's home meeting with Bolton Wanderers, Liam Manning had drawn all of his first four games as Oxford boss.
Disappointingly for Manning, his fifth game in charge resulted in a narrow 1-0 defeat with the contest settled by Dion Charles's seventh-minute strike.
Having picked up just four points in their 15-game winless run, the U's are currently in a precarious position, sitting just outside the drop zone on goal difference.
After scoring only two goals across their last five matches, Oxford will be fully aware that an improvement is needed in the final third in their final five fixtures.
With the U's desperate to claim all three points on Tuesday, they may be able to draw inspiration from the fact that they won their most recent home meeting with Portsmouth, recording a 3-2 victory in February last year.
Meanwhile, Portsmouth have avoided defeat in each of their last seven games, but a flurry of draws look to have ended their playoff hopes.
In Saturday's away meeting with Shrewsbury Town, Marlon Pack scored an 82nd-minute equaliser to cancel out Rob Street's opener, before Tom Flanagan was given his marching orders with four minutes remaining.
John Mousinho's side were unable to capitalise on the late red card, ensuring Pompey played out a third consecutive draw.
With four games remaining, closing the six-point gap to the playoffs seems unlikely, but Mousinho will still be keen to see his side extend their unbeaten run on Tuesday.
Pompey have been resolute on their travels this season, keeping nine clean sheets in their 21 away league games - only Sheffield Wednesday have recorded more.
Oxford United League One form:
L
D
D
D
D
L
Portsmouth League One form:
W
D
W
D
D
D
Team News
Oxford are without James Henry and Sam Baldock, who are both set to miss the rest of the season with injury issues.
Stephan Negru is also sidelined for the hosts, but Elliott Moore will retain his place in the side after returning from a head injury to feature in central defence on Saturday.
After featuring as substitutes against Bolton, Tyler Goodrham and Gatlin O'Donkor could both be brought into the starting lineup.
As for the visitors, they are still unable to call upon the services of injured duo Zach Swanson and Ronan Curtis, while Joe Morrell will serve the final game of a three-match suspension.
Mousinho brought Joe Pigott into the lineup for Saturday's draw, and the Ipswich loanee is expected to retain his place for the midweek encounter.
After coming off the bench in the second half against Shrewsbury, Michael Jacobs could be presented with a starting opportunity.
Oxford United possible starting lineup:
Eastwood; Long, Moore, Findlay, Brown; McGuane, Brannagan; Joseph, Browne, Goodrham; O'Donkor
Portsmouth possible starting lineup:
Macey; Rafferty, Raggett, Robertson, Ogilvie; Tunnicliffe, Pack; Dale, Pigott, Jacobs; Bishop