Both sides come into this clash on the back of league wins at the weekend, with the hosts particularly keen to take a first step towards a record-extending 14th cup triumph in the spring.
Ahead of their return to knockout football, Juventus sealed a second successive Serie A win over a close rival in the standings. In the round-ending Sunday evening kickoff, the Bianconeri saw off Sassuolo 3-1 thanks to late goals from Aaron Ramsey and Cristiano Ronaldo.
That win came just days after a crucial triumph over Milan at San Siro, getting Andrea Pirlo's men back on track in the Scudetto race following a disappointing series of draws - plus a calamitous loss to Fiorentina - before Christmas.
Even with Champions League football now on the back burner until February, Juve are inundated with fixtures - as in the coming days they must also contest the Derby d'Italia with Inter and the Suppercoppa Italiana final against a Napoli side that beat them in last term's cup final.
Increasingly decimated by injuries and illnesses, Pirlo will necessarily rely on his impressively deep squad against Genoa, as they aim for a fifth win in six games and a potential quarter-final with Sassuolo or Serie B side SPAL.
Progress is expected, as Juve's last Coppa Italia defeat against Wednesday's opposition came back in 1939 and the Piedmont giants have remained undefeated in all 10 cup ties between the two teams since.
Genoa have made it to the final 16 by virtue of wins over Catanzaro and city rivals Sampdoria in the third and fourth rounds respectively, but must now face the sternest test in Italian football.
Rank outsiders they may be, but the Grifone will travel to Turin buoyed by 'the Ballardini effect' - their returning coach (now on stint number four at the club) Davide Ballardini has overseen a much-needed upturn in results of late.
With two wins, a draw and just a solitary loss recorded since the experienced tactician took over in December, the change in a squad that previously looked doomed to the drop has been remarkable.
Before the departure of failed former boss Rolando Maran, the Rossoblu had conceded an average of two goals per game, but in their last four games they have let in just three altogether - including a clean sheet in Saturday's 2-0 win against Bologna.
Whether such improvements will be sufficient for the Ligurian side to cause a major cup shock at the Allianz Stadium remains to be seen though.
They will have to overcome the weight of precedent, as Juventus have put together a total sequence of 20 games unbeaten at home to Genoa in all competitions, including a 3-1 league win just a few weeks ago.
Juventus form (all competitions): DWLWWW
Genoa Coppa Italia form: WW
Genoa form (all competitions): DLWDLW
Andrea Pirlo is expected to rotate his diminished squad due to tight turnarounds between successive big games and a growing list of absences.
Paulo Dybala and Weston McKennie picked up injuries at the weekend, while defensive trio Juan Cuadrado, Alex Sandro and Matthijs de Ligt previously tested positive for COVID-19 and are self-isolating. In-form Federico Chiesa also suffered a knock against Sassuolo and is unlikely to start, as tactically versatile Pirlo could line up with a variant of his generally favoured 4-4-2.
Buffon's former Azzurri backup Federico Marchetti is generally Genoa's Coppa Italia goalkeeper, so Mattia Perin (on loan from Juventus) should be rested for the visiting side, who could be without both Luca Pellegrini and Goran Pandev on Wednesday.
The likely midfield trio in Ballardini's 3-5-2 will be Stefano Sturaro, Ivan Radovanovic and Valon Behrami, while up front Miha Zajc is expected to support either Destro or supposed Juve transfer target Gianluca Scamacca, with Uzbek striker Eldor Shomurodov waiting in the wings.
Juventus possible starting lineup:
Buffon; Danilo, Demiral, Chiellini, Frabotta; Bernardeschi, Rabiot, Bentancur, Arthur; Kulusevski; Ronaldo
Genoa possible starting lineup:
Marchetti; Masiello, Goldaniga, Bani; Zappacosta, Sturaro, Radovanovic, Behrami, Criscito; Zajc; Destro
We say: Juventus 2-0 Genoa
Though it is possible that Juventus could take their eye off the ball on Wednesday - given upcoming encounters with Inter and Napoli - the absence-afflicted Bianconeri can still field a fearsome 'second string', with Dejan Kulusevski and Federico Bernardeschi among those eager to take their chance.
Genoa's recent move away from the foot of the league table may have lifted their confidence, but a first win at the 13-times Coppa winners in over a decade represents a bridge too far.