Justin Richards is set to continue in attack for Oxford as James Constable serves the second game of his three-match ban.
The 32-year-old started for the U's against Sheffield United on Saturday having just returned for a second loan spell with the club on Friday.
With fellow forwards Deane Smalley and Jon-Paul Pittman still sidelined and Constable suspended, the Burton forward is set to continue alongside Tom Craddock at the Kassam.
But one new signing who will not feature against Southend is loanee Lewis Montrose who is cup-tied having already featured in the competition for parent club Gillingham this season.
Manager Chris Wilder is unlikely to make too many changes to his side but could recall Michael Raynes in the heart of defence and rest Michael Dubbery.
"We've just got to go and not get knocked out of two cup competitions in the space of a week," he told the Oxford Mail.
Midfielder Marc Laird is cup-tied for Southend.
Laird, who turned his loan switch from Leyton Orient into a permanent deal on Friday, sits out at the Kassam Stadium having played earlier in the competition for his former club.
On-loan striker Britt Assombalonga will be assessed ahead of the tie having missed Saturday's 2-2 FA Cup third-round draw at home to Brentford with his troublesome ankle and shin injury.
However, should Assombalonga even be passed fit then he will face a tough ask regaining his starting spot after Barry Corr stepped in and bagged a brace against the Bees to rescue an FA Cup replay.