MK Dons come into this match in need of some momentum due to going three matches without a victory in League Oneunder Liam Manning, which has left them in the relegation zone.
In their last outing, the Dons were on the receiving end of a 3-1 loss to Barnsley courtesy of goals from Herbie Kane, Adam Phillips and Jordan Williamswhich cancelled out a Mo Eisa reply.
Nevertheless, they managed to top Southern Group C in the EFL Trophy with six points from three matches overcoming Cheltenham Town, West Ham United Under-21s and Walsall in the table.
Victories over West Ham U21s and Walsall were enough to secure a place in the knockout phase on goal difference, while their only defeat in the group came to Cheltenham Town on matchday one.
MK Dons manager Manning will be hoping for a swift response to their recent demise on cup duty this Tuesday as they look to go deep into the competition of which they were one-time winners in 2007-08.
Newport travel across the border looking to spring an upset and book their place in the next round following a strong group-stage performance in the EFL Trophy.
They achieved a credible finish in Southern Group F, accumulating six points from three matches in a group containing Forest Green Rovers, Exeter City and Southampton Under-21s.
Two wins against Exeter and Southampton U21s were enough to bank a place in the second round of the tournament, with their only loss in the group occurring at home to Forest Green on matchday two.
Building an extensive cup run could be of interest to the Exiles in light of their position in League Two, where they sit in 18th, owing to an indifferent start to their league season.
Though they face a tough task playing a side that are one division higher in the English pyramid, Graham Coughlan will fancy his chances of springing a shock.
MK Dons may look to give several fringe players some minutes in their EFL Trophy tie against Newport on Tuesday evening.
Striker Will Grigg could be offered an opportunity to impress in attack in place of Mo Eisa, while Irishman Dawson Devoy is likely to be given some minutes in midfield.
Goalkeeper Franco Ravizzoli will hope to be selected ahead of Jamie Cumming between the sticks, while Aston Villa loanee Louie Barry may be rested in favour of Darragh Burns on the flank