Wahbi Khazri and Bryan Oviedo will start for Sunderland against Carlisle United on Tuesday night.
Jack Rodwell and Robbin Ruiter could also make their first competitive appearances of the season, with Simon Grayson set to ring the changes following the 2-0 defeat against Leeds United.
Grayson is eager to avoid fatigue setting in amongst his established players but has insisted that those who perform against the Cumbrians will start against Barnsley on Saturday.
He said: "Oviedo will play on Tuesday night, Wahbi will play, Rodwell could possibly play.
"I don't give away my team, but there will be quite a few changes. I've got to get the balance right. We've played four games in nine days.
"But regardless of who we play on Tuesday night, whoever comes into the team won't be there to make up the numbers.
"They will be good footballers who have played a lot of Premier League football, and international football. We might be changing it around, but we won't be fielding a team full of kids.
"Our intention is to win this game, not play the U23s as some other clubs might do."
Brendan Galloway will miss out after picking up an injury against Leeds, but James Vaughan will be available. The 29-year-old hurt his ankle in the warm-up on Saturday evening, a recurring problem but not one that will keep him out of action.
Grayson added: "The first round of the cup was an intention to get through the round, play players who needed more game time and understanding of those situations and combinations. Now we’re a little further down the line, there will be changes to the team because of the schedule we’ve had.
"But ultimately whoever is picked on Tuesday night will be told the shirt is yours, you perform and you will be in the team for the Barnsley game. That’s always been the case from day one, we said if you’re in the team for the first game of the season, do enough to keep it, I’ve stuck to my word, they played well so we’ve gone four games and haven’t changed.
"There will be changes now and if players perform they’ll have a right to keep the shirt for Saturday, that needs to be a massive motivation for those coming in."