While the Grifone have seamlessly adapted to life back in Serie A after switching places with Samp last season, their second-round opponents are currently struggling in Italy's second division.
Match preview
Taking place at Stadio Luigi Ferraris - commonly known as Marassi - which both clubs share, the city derby between Genoa and Sampdoria is the oldest in Italian football, with the first contest being played out back in 1902.
While Genoa have been historically the more successful side, both have had many ups and downs over recent years, and in the summer of 2023 the Grifone were promoted to the top flight just as Samp sunk down into Serie B.
It was Alberto Gilardino that led them back to the promised land - and kept them there last season - before starting the current campaign by taking five points from as many matches so far.
Most recently, Genoa followed a last-gasp draw against Roma with Saturday's 2-0 defeat at newly promoted Venezia, leaving them 16th in the early Serie A standings.
Gilardino will look to bounce back straight away, as his team face two important fixtures over the next few days: just after the derby, they must host Juventus in the league.
After beating Serie B side Reggiana in last month's first round, Genoa now intend to pile more misery upon their fiercest foes by knocking them out of the cup and fixing a date with Roma in the last 16.
While Genoa have eight more Scudetti to their name than Sampdoria, they still trail the Blucerchiati by three in terms of cup wins: during Samp's 1980s to '90s golden era, they lifted the Coppa Italia no fewer than four times in a decade.
When the sides most recently met - during the 2021-22 campaign - they also beat their Rossoblu rivals in both Serie A derbies, but since then it has been a sorry tale of decline.
Relegated last year, Samp failed to bounce back at the first attempt, losing in the playoffs, and after a slow start to this season they sacked high-profile head coach Andrea Pirlo.
Having since hired Andrea Sottil, who was fired by Udinese in October of last year, the Blucerchiati are still struggling to live up to their lofty reputation, sitting 17th in the Serie B standings.
However, they finally picked up their second win of the season on Saturday, beating Sudtirol 1-0 via Lorenzo Venuti's goal. The other was back in early August, when they overcame Como on penalties to set up this week's cup derby.
Genoa Coppa Italia form:
W
Genoa form (all competitions):
W
D
W
L
D
L
Sampdoria Coppa Italia form:
W
Sampdoria form (all competitions):
D
L
L
D
L
W
Team News
While Alberto Gilardino would usually rotate his squad heavily for a midweek cup clash before facing Juventus, the nature of Wednesday's tie may mean he names a relatively strong starting XI.
Two places in attack are up for grabs, with Vitinha, Caleb Ekuban and Andrea Pinamonti heading the queue for selection.
Junior Messias is still sidelined and Fabio Miretti remains a major doubt, while Ruslan Malinovskyi suffered a season-ending injury at the weekend and must be replaced in midfield.
Sampdoria's precarious position in Serie B means that Andrea Sottil could make more changes to keep key men fresh for Sunday's game against Modena.
The Blucerchiati are likely to line up in a 3-5-2 formation, as Gennaro Tutino and Massimo Coda compete with ex-Liverpool striker Fabio Borini for the nod to start up front.
Alessandro Bellemo, Gerard Yepes and Lorenzo Venuti are all doubtful due to injuries sustained at the weekend.
Genoa possible starting lineup:
Leali; Vogliacco, Bani, Matturro; Zanoli, Frendrup, Badelj, Thorsby, Martin; Ekuban, Pinamonti
Sampdoria possible starting lineup:
Silvestri; Ferrari, Romagnoli, Vulikic; Bereszynski, Benedetti, Vieira, Kasami, Barreca; Borini, Coda
We say: Genoa 3-1 Sampdoria
Liguria will come to a standstill for 90 minutes on Wednesday evening, as the latest Derby della Lanterna plays out - but only Genoa fans will be celebrating at the final whistle.