The League Two outfit have beaten Leicester City and drawn against Tottenham Hotspur in recent years, and the West Ham United will be keen to avoid becoming the latest Premier League side to struggle at Rodney Parade.
Manuel Pellegrini is likely to make 11 changes to the team that won 3-1 away at Watford on Saturday.
Summer signings Roberto, Goncalo Cardoso and Albian Ajeti could make their debuts as West Ham look to book their place in the third round of the competition.
Players who have received limited minutes in the league are also likely to start, with Pablo Fornals, Carlos Sanchez and Pablo Zabaleta all expected to feature.
The home side lies fifth in League Two after making an unbeaten start to their campaign.
Mike Flynn's side have drawn three and won two so far, beating both Plymouth Argyle and Crewe Alexandra 1-0 at home.
They have already seen off higher division opposition in the Carabao Cup this season, beating Gillingham of League One on penalties in the first round.
The Hammers have had a mixed start to the season and currently have four points following a loss to Manchester City, a draw away at Brighton & Hove Albion and a win against Watford.
West Ham's supporters expect a cup run this season as the club aims to win its first domestic cup competition since 1980.
One to watch: Albian Ajeti
The 22-year-old Swiss international arrived from Basel for £8m this summer and will be hoping to impress as he looks to cement a place in the side.
As expected, the young forward has so far served as third choice behind Sebastien Haller and Javier Hernandez, however, a good display in the cup could be rewarded with game time in the Premier League.
Ajeti is known for his clinical ability in front of goal and is also able to use his strength to hold off defenders; a physicality that will be required against a tough Newport County defence.