Rafa Benitez returns to England with his new side having dropped just two points all season, but faces a Gunners outfit which has won eight on the bounce in all competitions.
Both teams secured 2-1 wins in the opening round of matches and will square off in competitive action for the first time at the Emirates Stadium.
Arsenal is on a nine-game winning run in all competitions, with defeat to Aston Villa on the opening day of the Premier League season the last time the London club tasted defeat.
The club's latest success came in Saturday's 2-1 victory away to Swansea City, with a first professional goal from Serge Gnabry and an effort from in-form Aaron Ramsey - his fifth in his last four games - proving enough for the points.
Manager Arsene Wenger is confident that three points against the Serie A side will leave the team in a strong position to reach the round of 16.
"If we win the second game we know we can qualify," he said. "I wouldn't say it is already a decisive game - but it is a game that will have a great bearing on who qualifies.
"If we deal with that situation then we will be in a very positive mood to finish the job."
Arsenal's form has been all the more impressive with an injury list that includes Lukas Podolski (hamstring), Santi Cazorla (ankle) and Theo Walcott (stomach) among the players on the sidelines.
Defeating Napoli will be no easy task, as Rafael Benitez's tenure at the Stadio San Paolo has started in terrific fashion.
Napoli has won five and drawn one of its six Serie A fixtures, and began its Champions League campaign with an impressive triumph over last season's runner up, Borussia Dortmund.
Goals from Gonzalo Higuain and Lorenzo Insigne did the damage on that occasion, and the club claimed the maximum haul despite Camilo Zuniga's late own goal.
Despite the excellent start, Benitez believes the side has yet to reach its full potential, but says the club is confident of its chances in London.
"We talk with the team every day and we know that we are at 75 percent," he told the club's official website.
"Now we must continue to grow. I know that we can and we must be competitive to try and win against all opponents. That is what we will try to do in London against Arsenal."
Christian Maggio (knee) is Benitez's only absentee, with Higuain set to start against a club he came close to joining over the close season.
Reports suggested that Arsenal were ultimately unwilling to match Napoli's fee for the former Real Madrid man, paving the way for a move to Serie A, while the Argentinian was afforded a frosty reception when the Naples club played against Arsenal in preseason during the Emirates Cup.