This year seeking a seventh cup win, the Azzurri welcome their Sicilian counterparts to Stadio Maradona fresh from a goalless draw with Juventus.
Match preview
Taking 10 points from their last four games has seen new-look Napoli recover from a shaky start to Antonio Conte's reign, in which they needed penalties to shake off Serie B side Modena in the Coppa Italia before losing 3-0 to Hellas Verona in their league opener.
Most recently, the Azzurri saw a three-match winning run ended in Turin, where they were held to a 0-0 draw by Juventus, but they had previously averaged three goals per game in the process of picking up nine points from a possible nine.
With former star Victor Osimhen exiled in Istanbul, Conte has turned to old favourite Romelu Lukaku and irrepressible winger Khvicha Kvaratskhelia to lead his attack, and a challenge for the top five is Napoli's minimum requirement.
After failing to qualify for Europe at the end of a calamitous 2023-24 campaign, the Campanian club can also concentrate on trying to win the Coppa Italia for the first time in five years.
While Conte may have half an eye on Sunday's league game against Monza, first he will expect his team to take care of business against second-tier opposition in the cup.
Palermo may be a Serie B side at the moment, but they have ambitions of joining Napoli in Italy's top flight next season, having been acquired by the far-reaching City Football Group in the summer of 2022.
Last season, the Sicilian club missed out in the playoffs, so they are now building towards another promotion push under former Sassuolo coach Alessio Dionisi, who was sacked before the Neroverdi were relegated last term.
Dionisi did lead Empoli up to Serie A in 2021, though, and his new side sit in mid-table after five games of the current campaign.
Like Napoli, Palermo have recovered from a sluggish start, and they have just put together a four-game unbeaten streak; unlike Thursday's hosts, they have yet to lift the Coppa Italia throughout their 124-year history.
It is unlikely that the Rosanero will finally end that wait next May, but they will still dream of meeting Lazio in the last 16, which would be their prize for following up last month's first-round win over Parma by beating Napoli at the Maradona.
Napoli Coppa Italia form:
W
Napoli form (all competitions):
W
L
W
W
W
D
Palermo Coppa Italia form:
W
Palermo form (all competitions):
L
L
W
D
W
D
Team News
After selecting a fairly consistent lineup so far, Antonio Conte will surely switch things up in midweek, with Sunday's game against Monza in mind.
Scottish star Scott McTominay made his first Napoli start against Juventus, but compatriot Billy Gilmour could be among several players brought in to freshen up the hosts' XI on Thursday evening.
Conte has few absences to concern him, though Alex Meret sustained a minor thigh injury at the weekend, so Elia Caprile is set to start between the posts.
Meanwhile, Palermo can welcome back Fabio Lucioni, who has returned to full training after his long layoff with a hip injury; however, French midfielder Claudio Gomes is a major doubt.
While summer signing Thomas Henry started again in last week's home draw with Cesena, confirming his place at the top of the attacking hierarchy, captain Matteo Brunori may be recalled in the cup.
Palermo's top scorer for the last three seasons has recently been relegated to the role of super-sub, but he might now be handed a chance to change Alessio Dionisi's thinking.
Napoli possible starting lineup:
Caprile; Jesus, Marin, Buongiorno; Mazzocchi, Gilmour, McTominay, Spinazzola; Neres, Raspadori; Simeone
Palermo possible starting lineup:
Sirigu; Diakite, Nedelcearu, Nikolaou, Pierozzi; Segre, Saric; Insigne, Blin, Le Douaron; Brunori
We say: Napoli 2-0 Palermo
Even Napoli's second string - if selected by Antonio Conte - has a strong look, since some summertime spending rejuvenated a slightly jaded squad.