United top their group with eight points after four games and, with Ben Dawson's side currently one point ahead of second-placed Southampton, a victory over the Saints will secure Newcastle's place in the round of 16 with a game to spare.
United have already faced Southampton on three occasions this term, but are yet to claim a win following a Premier League Cup draw on the South Coast as well as two losses in Premier League 2.
Newcastle are in rich attacking form, scoring 37 goals so far in Premier League 2, with 13 goals in their last three fixtures.
However, Dawson's squad face a Southampton side who have shipped just 12 goals in Division Two.
Admission is £3 for adults and £1 concessions. The match, taking place at Whitley Park, is free for season ticket holders and members.