The Argentine hit man will take the pitch and face up against Arsenal's current striker Olivier Giroud, the man he had been tipped to replace in the Gunners' attack over the summer.
As Arsene Wenger and Rafa Benitez have each strictly employed a 4-2-3-1 formation this season, it is almost certain that the opposing strikers will be fielded in corresponding positions: up front and supported by an attacking midfield trident.
Both Giroud and Higuain have enjoyed a productive start to their respective domestic campaigns, with the former netting four times in six appearances and the latter bagging three goals in the same number of games.
The Frenchman holds the advantage thus far in terms of Squawka Performance Score domestically, with a tally of 152 in the Premier League to his Partenopei rival's 129 in Serie A.
However, the Arsenal man limped to a disappointing figure of -42 in the London outfit's first Champions League encounter with Marseille, whilst Higuain registered a Performance Score of 58, snatching the crucial opener in Napoli's famous 2-1 triumph over Borussia Dortmund at the Stadio San Paolo.
In truth, it remains to be seen whether Giroud can replicate the success he has had in the Premier League in Europe's elite competition and prove definitively that he can fulfil the goalscoring duties that Higuain was targeted this summer to share.
However, although they play in the same role in their managers' tactical set-ups, the players have distinct styles, as evident by Giroud's more discerning nature with the ball at his feet and far superior record in the air.
The ex-Real Madrid forward has beaten his man more often with eight successful take-ons to Giroud’s four - perhaps this suggests that the Argentine is more inclined to risk losing possession having attempted 17 overall in comparison to just seven from the Arsenal forward.
However, the France international has won 59% of his total 64 headed duels in the Premier League heading into the midweek contest, with Higuain having emerged the victor in only four of 18 aerial battles in Serie A.
Curiously, none of Giroud's goals in 2013-14 have been scored with his head, all four instead having come off his left foot, while the Argentine has similarly struck all three of his league goals with his right foot, though his 29th-minute opener against Dortmund was a headed effort.
With regards to hitting the target, Higuain has achieved a shot accuracy of 53% in Italy’s first division to date, dwarfing his adversary’s rate of 38%, and they have taken a similar number of total shots: 15 and 16 respectively.
On the creative front, Giroud has fared better than the Argentine, creating 10 chances to the San Paolo-based stiker’s eight. While Giroud has two assists, to Higuain's one, perhaps this indicates that the Frenchman is better at linking the play than the Argentine.
The duo are also blessed with plenty of talent in attacking midfield, particularly in the form of a pair of top playmakers, blockbuster deadline-day capture Mesut Ozil for Giroud and Slovakian talisman Marek Hamsik for Higuain.
Pacey trio Lorenzo Insigne, Dries Mertens, and Jose Callejon provide extra support for the Argentine, whilst Arsenal will be without Santi Cazorla, Theo Walcott, and Alex Oxlade-Chamberlain on the day, but have Tomas Rosicky back from injury to aid Giroud.
The subtext of Arsenal’s failed summer pursuit of Higuain will of course see the two strikers under the microscope throughout the match, and although they do not possess identical playing styles, Benitez and Wenger’s corresponding tactical set-ups see them thrust into similar roles.
Both teams have their defensive frailties despite early success with a combined 14 goals conceded in all competitions, but either striker could be the difference in this glamorous European tie.