With a perfect record in the Italian top flight, the Azzurri will seek to add to their single point gained on the opening night, while their visitors sit bottom of the early Group C table.
At the weekend, Napoli stayed top of the table in domestic football by making it six wins from six after a 2-0 win over Cagliari - with star striker Victor Osimhen on the scoresheet again for the home side at Stadio Maradona.
Their so-far perfect start to the Serie A campaign may have been prolonged at the Sardinian side's expense, but Luciano Spalletti's men are now tasked with posting their first win in Europe this term.
Napoli appeared to be heading for a loss in Leicester City on the opening matchday earlier this month, but two second-half strikes not only salvaged a draw for the Partenopei but also bolstered the Nigerian's growing reputation as a forward to be feared across the continent.
His six goals in as many competitive matches have been instrumental in the Neapolitans' electric start, which has seen them brushing off all-comers with a series of impressive performances.
Netting 16 times in six league games - while conceding only two - demonstrates Spalletti's success in ensuring a smooth transition since he took over an underachieving team in the summer.
Last year, Napoli topped their group but were then eliminated in the last 32 by European debutants Granada, and later missed out on Champions League qualification on the final day of the season. Therefore, they will now be determined to take care of business at the Maradona, where they have remained unbeaten since January.
Already considered outsiders to progress to the knockout stages, being joined in Group C by both Leicester and Napoli, in the opening match of the competition (held 24 hours before the other fixtures) Spartak Moscow were beaten by Legia Warsaw on home soil.
Having failed to hit the net despite 23 efforts on the visitors' goal, the Russian side went down to a stoppage-time strike from Legia's Lirim Kastrati, as the Polish champions escaped the Otkritie Arena with a 1-0 win.
The Muscovites had previously fallen to a 2-0 aggregate defeat against Benfica in Champions League qualification and so dropped down to Europe's second-tier club competition, in which they are now aiming to reach the knockout rounds for the first time since 2010-11.
Currently sitting eighth in the Russian Premier League - already ten points behind leaders Zenit - the Red and Whites won 2-0 against Ufa on Saturday, following a derby defeat to CSKA just a few days earlier.
They now turn their attention to the Europa League, but including group stages and knockout rounds only, Spartak have come out on top in only four of their last 23 European matches - so the size of coach Rui Vitoria's task is significant.
Fans with long memories may recall their club being paired together with this week's opponents once previously, in the 1990-91 European Cup second round. On that occasion, Spartak prevailed on penalties after both games finished goalless, and the second leg in Moscow proved to be Diego Maradona's farewell appearance in the competition.
Now Vitoria leads the current team to Naples, where they will walk out at the famous old stadium which now bears the great Argentinian's name, in hope more than expectation of a positive result.
Napoli coach Luciano Spalletti finally had midfielder Diego Demme back in the fold on Sunday, with the German making a brief appearance from the bench for the final few minutes against Cagliari. Therefore, he may be offered another appearance, should Spalletti choose to rest one of his engine room operators.
In the attacking triumvirate, Victor Osimhen is set to step aside from the centre-forward role, allowing Andrea Petagna to deputise.
Spartak will again be without centre-back Paval Maslov and forward Georgi Melkadze, who are suffering with respective foot and muscle issues, while both Jorrit Hendrix and Roman Zobnin are major doubts for the Red and Whites.
Napoli possible starting lineup:
Meret; Di Lorenzo, Manolas, Koulibaly, Rui; Elmas, Ruiz, Zielinski; Insigne, Petagna, Politano
Spartak Moscow possible starting lineup:
Maksimenko; Caufriez, Dzhikiya, Gigot; Moses, Umyarov, Bakaev, Ayrton; Ponce, Sobolev, Promes
We say: Napoli 2-0 Spartak Moscow
Excelling at both ends so far under Luciano Spalletti - former boss of Spartak's domestic rivals Zenit - there is little doubt that Napoli can overcome their visitors without too much trouble, even if they rotate their resources.
Coming up against an abundance of attacking options allied to a well-drilled defence means that Spartak will take the long journey home empty-handed and already staring elimination in the face.
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