Newport have knocked out Swansea City, Cambridge United and Watford to reach round four, while Newcastle have overcome Blackburn Rovers and Morecambe en route to the last 16.
Having reached the fourth round of the EFL Cup for the first time in the club's history, Michael Flynn's current crop of Newport players now have the chance to etch their names into the history books when they welcome Premier League opposition to Rodney Parade.
Prior to the 2020-21 campaign, Newport had only ever gone as far as the second round - the stage where they had been knocked out three times in a row between 2017 and 2019.
Whatever happens on Wednesday night, the League Two outfit can be incredibly proud of what they have achieved as the only non-Premier League or Championship side left in the competition.
Newport's preparations for this historic encounter could hardly have gone smoother - Flynn's men enjoyed a 2-0 victory over Bolton Wanderers at the weekend and have taken seven points from a possible nine in the fourth tier thus far.
Steve Bruce's men have endured a mixed start to their Premier League campaign - winning one, losing one and drawing one - but the Magpies must now turn their attention to the EFL Cup as they bid to avoid a shock exit to League Two opposition.
As is the case with Newport, Newcastle have also been sent packing in the second round three times in a row before this season, and the Magpies have never advanced further than the quarter-final stage in this competition.
Newcastle overcame Morecambe 7-0 in the third round to set up a tie with Newport, so while the Exiles faithful can be allowed to dream of a famous victory in midweek, Flynn's men will no doubt be preparing for a Newcastle onslaught.
The two clubs have met three times down the years, with Newport prevailing in the last fixture back in 1947, but Newcastle recorded a 13-0 victory when the clubs faced off in October 1946 - their biggest win in the club's 127-year history.
Newport County EFL Cup form: WWW
Newport County form (all competitions): LDWWWW
Newcastle United EFL Cup form: WW
Newcastle United form (all competitions): WWLWD
Tristan Abrahams - who bagged one against Watford and a brace against Bolton - already has five goals to his name this season in all competitions, with three of those coming in the EFL Cup. Only West Ham United's Sebastien Haller has more in the competition.
As for Newcastle, Bruce is expected to shuffle the pack for the midweek showdown, with the Magpies manager already forced into one change owing to Matt Ritchie's injury against Tottenham.
Newport County possible starting lineup:
King; Cooper, Dolan, Demetriou; Shephard, Sheehan, Labbadie, Collins, Haynes; Amond, Abrahams
Newcastle United possible starting lineup:
Gillespie; Krafth, Lascelles, Fernandez, Lewis; Murphy, Longstaff, Hayden, Fraser; Carroll, Joelinton
We say: Newport County 1-3 Newcastle United
Newport have already gone further than they ever have before in this competition and have every right to dream of making the quarter finals. While Flynn's side deserve a huge amount of credit for overcoming two Championship sides en route to round four, Newcastle showed no mercy to Morecambe and will simply have too much quality for the League Two outfit, so we expect the Newport journey to end here.