Meanwhile, the young Magpies will want to continue their fine form after winning their last three matches in all competitions.
Match preview
Rotherham United will head into the midweek fixture in a positive mood after bouncing back from a four-game winless run (D3, L1) to clinch maximum points in their last two league outings.
Sam Nombe scored a stoppage-time winner to snatch all three points against Cambridge United, before he found the net again in Saturday's narrow 2-1 victory over Reading.
The 25-year-old forward cancelled out Lewis Wing's opener, before Hakeem Odoffin netted a 56th-minute winner to guide Rotherham to back-to-back victories for the first time since October 2022.
Steve Evans's side will now turn their focus to EFL Trophy action, with the Millers looking to build upon the 2-0 win they recorded in their opening group game against Mansfield Town.
After lifting the silverware in their most recent EFL Trophy campaign in 2021-22, Rotherham are unbeaten in their last nine matches in the competition since losing to Leeds United in November 2019.
Newcastle U21s are competing in the EFL Trophy for an eighth consecutive season, with the Magpies looking to progress from the group stage for just the second time.
Their previous knockout-round appearance took place in 2018-19 when they won three consecutive games to finish top of their group.
They are currently focused on the 2024-25 edition of the EFL Trophy as they bid to advance from a group which contains Bradford City, Rotherham and Mansfield Town.
Newcastle U21s already have two points on the board after Josh Donaldson netted a 92nd-minute equaliser to secure a draw with Bradford, before the Magpies went on to win the subsequent penalty shootout to pick up a bonus point.
The Magpies are now focusing on Tuesday's away trip, and they will travel to the New York Stadium in a positive mood after winning their last three competitive matches against Blackburn Rovers Under-21s, Halifax Town and Aston Villa Under-21s.
Rotherham United EFL Trophy form:
W
Rotherham United form (all competitions):
D
D
L
D
W
W
Newcastle United Under-21s EFL Trophy form:
W
Newcastle United Under-21s form (all competitions):
Team News
Rotherham defender Sean Raggett is unlikely to be involved after missing the last three matches with a knee injury.
Liam Kelly is also set to sit out Tuesday's fixture, but there is hope that he and Raggett will be available for Saturday's league meeting with Peterborough United.
With one eye on that league clash, Evans is expected to make wholesale changes for the EFL Trophy outing, with Dillon Phillips, Cohen Bramall, Zak Jules, Shaun McWilliams and Jordan Hugill among those who could come into the starting lineup,
As for the visitors, they are set to line up with a back four of Rory Powell, Ciaran Thompson, Cathal Heffernan and Dylan Charlton.
At the opposite end of the pitch, Parkinson will offer one of the main attacking threats after scoring a brace against Aston Villa Under-21s and netting in the opening EFL Trophy game against Bradford.
Rotherham United possible starting lineup:
Phillips; Rafferty, Jules, McCart, Bramall; Holmes, McWilliams, McDonald; Hungbo, Nombe, Hugill
Newcastle United Under-21s possible starting lineup:
Harris; Powell, Thompson, Heffernan, Charlton; Huntley, Stanton, Hernes; Parkinson, Emerson, Donaldson