All eyes will be on the final matchday in Group F as two from three teams can qualify for the knockout stages. The Gunners only need to avoid a defeat of three goals or more against the Naples-based side to progress. If they suffer a heavy defeat, Diego Maradona's old club will progress in their place, but only if Borussia Dortmund manages to beat Olympique Marseille as expected.
Over the years, Arsenal have faced Italian opposition 28 times and have only lost six times. The odds are in Arsene Wenger's favor especially as Napoli have to win by three goals.
Here, Bleacher Report looks at the key tactical battles that will shape the clash as Napoli go face to face with the Premier League's pace setters, Arsenal.
All statistics from WhoScored, UEFA and Soccerbase.
Arsenal were closely linked with Gonzalo Higuain before Rafael Benitez and Napoli snapped up the ex-Real Madrid striker.
It is amazing to think now that if Arsene Wenger had signed the Argentinean he might not have captured Mesut Ozil from Real Madrid. Where would the Gunners be now without the influential attacking midfielder?
But I digress.
Higuain missed his team's 2-0 capitulation at the Emirates Stadium. There, Arsenal put in a complete performance and obliterated Napoli despite the lowly score line. Things will be very different this time around, particularly for Arsenal's defenders, as Benitez will be able to call upon his most important player.
The entire system at Napoli is based around Higuain as the focal point up front. He leads the line well. The 26-year-old is deceptively strong and maintains possession under pressure, he constantly brings supporting midfielders into the game and has a keen eye for goal.
Over the course of his career he has scored 148 goals in 322 matches and this season he has bagged 10 goals in 16 games.
Laurent Koscielny will be tasked with keeping a close eye on the Argentinean international. The Frenchman has developed into one of Arsenal's most important players over the last 12 months. He has become a consummate man-marker and is creating a growing reputation of being able to close strikers out of the game.
He will need to be at the top of his game to keep Higuain quiet. Koscielny made a couple of key mistakes against Borussia Dortmund over the course of their two games and they led to clear goal scoring chances. Higuain is ruthless in front of goal and will punish the Gunners if he is let free.
With Napoli needing at least three goals to progress they are sure to utilize Higuain at every opportunity, thus Koscielny could well become Arsenal's most important player.
Carl Jenkinson and Lorenzo Insigne will have much to prove when they face each other in Matchday 6.
Both of these players are beginning their careers at the highest level and are relatively inexperienced when it comes to big game pressure situations.
Jenkinson will deputize for veteran right-back Bacary Sagna who is out injured. Sagna's loss is a big blow because he has been instrumental in everything that is good about Arsenal this season. His experience has been vital and while he has passed that all important threshold at 30, he is playing with the energy of a man 10 years his junior.
To demonstrate how important Sagna has been this term all one has to do is realize that 47 percent of Arsenal's attacks initiate down the right hand side with the full-back the key instigator. He is better offensively and defensively than Jenkinson, who can prove haphazard, and he will be missed.
Jenkinson will do well to fill the void left by Sagna but he is regarded as a regular England international of the future and this game will go some way to proving that point.
For his part, Insigne is a vibrant and dynamic attacking left-sided midfielder. He broke into Napoli's team last season and has continued in the same vein this term. Also just 21 years of age, Insigne is one of the less experienced men in the Napoli team, but he is also expected to deliver.
He likes to challenge his opposite number and will try to get around Jenkinson towards the backline to cross for Gonzalo Higuain. He is comfortable on the ball, extremely quick over short distances and possesses vision that belies his tender age.
Insigne has the potential to cause huge problems for the less-experienced Jenkinson and will try to expose the Arsenal man in one-on-one situations.
This fact will probably temper Arsene Wenger's thinking on the right-side of midfield and it would be no surprise to see the extremely hard working Tomas Rosicky get the nod over Theo Walcott. Rosicky works back constantly and will help Jenkinson at every opportunity.
Whoever gets on top in this battle will feed into the battle between Laurent Koscielny and Gonzalo Higuain so this are of the pitch will be vital in the overall fight for dominance.
Gokhan Inler will be the man with the toughest job on the pitch come Wednesday night. The 29-year-old highly disciplined Swiss international is a conventional box-to-box midfielder, but he also excels in a defensive role for club and country.
Considering that Marek Hamsik will miss the match, much of the midfield onus will be placed upon Inler. His ability to read the game from a defensive standpoint makes him the ideal man to go toe-to-toe with Mesut Ozil.
Inler's main job will be to patrol the central midfield area in front of his back four. If he can control this area and force Ozil out wide, the German's influence will lessen. However, if Ozil can gain the upper hand then Napoli are in for a long night as the likes of Tomas Rosicky, Santi Cazorla and, lest we forget to mention, the irrepressible Aaron Ramsey will bomb forward to support Ozil and Olivier Giroud.
Central midfield will become the battle ground where this game is won and lost.
Inler, like Mikel Arteta, is exceptional in possession and rarely gives the ball away. Unlike Arteta, however, he likes to use long passes to the likes of Lorenzo Insigne and Jose Callejon. Ozil will have to be aware of this potential weapon. If there is a weak point to his game it can be found in the fact that he can give away needless free kicks.
Ozil will need no introduction to Arsenal or Napoli's fans. The German has all the skills needed to be a world-class No. 10. He works incredibly hard, both defensively and offensively, and is always available to receive the ball regardless of the danger surrounding him. He is one of the bravest players in the Arsenal line-up and never shirks his duty.
Inler will look to make his midfield battle with Ozil a war of attrition as the German is simply not built for those conditions. However, Ozil is far too intelligent a player to fall for such base tactics. Inler will therefore need to impose his game upon the Arsenal man by other means.
The battle to control midfield will be extremely tight.
Arsenal knows that if they score just one goal then the match is all but over.
Expect the Gunners to tear into Napoli right from the off, with Benitez's team trying to catch the Gunners on the break as they try to weather the storm.
The first 20 minutes will be key and the foundation for victory will be laid by Inler and Ozil in what could prove to be an incredibly exciting match.