While the Sardinian side have picked up just two points so far, Cremo are flying high in Serie B, just months after they missed out in last season's playoff final.
Match preview
Still seeking their first Serie A win of the new season, Cagliari were beaten 2-0 by undefeated Empoli at the weekend, leaving them at the foot of the standings after five matches.
Davide Nicola welcomed his old club to Sardinia in hope of finally getting off the mark, but his new side have now lost their last three matches and have scored only one league goal so far.
Fans of the Rossoblu are accustomed to slow starts, as last year they managed just one goal after five rounds under Claudio Ranieri and were still without a victory; eventually, they climbed their way towards safety.
However, there will surely be some concern in the camp, so Nicola will be keen to avoid a confidence-destroying cup upset in midweek, ahead of an upcoming league game against possible relegation rivals Parma.
Coppa Italia runners-up in 1969, but never winners of Italy's national knockout competition, Cagliari saw off Carrarese in last month's first round, with goals from Roberto Piccoli, Leonardo Pavoletti and Matteo Prati sealing progress to this stage.
When these teams last met in the Coppa, just under four years ago, Cremonese were beaten 1-0 in the second round by Cagliari.
The Lombardy club will try to reverse that outcome on Tuesday evening, having made a fast start to their latest attempt at escaping Serie B, where they currently sit four points shy of top spot.
At the weekend, Tommaso Barbieri's late winner secured a 2-1 win over Catanzaro - Cremo's victims in June's playoff semi-finals, before they were beaten to promotion by Venezia.
Having won half of their away fixtures in the league last season - enough to post Serie B's second-best record - and now two from three this term, the Grigiorossi are sure to fancy their chances against a team that has just lost back-to-back home games.
Despite coming up short in 2023-24, Giovanni Stroppa remains in charge, and his Cremonsese side started the new campaign by beating Bari on penalties in the Coppa Italia first round, setting up this week's clash in Cagliari.
Cagliari Coppa Italia form:
W
Cagliari form (all competitions):
W
D
D
L
L
L
Cremonese Coppa Italia form:
W
Cremonese form (all competitions):
L
W
L
W
D
W
Team News
With Serie A safety being his top priority, Davide Nicola is set to rotate his Cagliari squad ahead of next week's game against Parma.
Midfielder Matteo Prati has recently been sidelined by an ankle problem so may not be risked, but fringe players such as Nicolas Viola, Jakub Jankto and Michel Adopo will most likely come into contention.
In attack, Gianluca Lapadula and veteran super-sub Leonardo Pavoletti could replace out-of-form front pairing Roberto Piccoli and Zito Luvumbo.
Meanwhile, Cremonese boss Giovanni Stroppa has several absences to concern him, as Luca Ravanelli, Cristian Buonaiuto, Federico Bonazzoli and Federico Ceccherini are all injured.
Zan Majer and Marco Nasti will hope to fully recover from illness, though, and Georgian defender Luka Lochoshvili will be back from suspension.
Cagliari possible starting lineup:
Ciocci; Zappa, Palomino, Obert; Azzi, Gaetano, Adopo, Jankto, Zortea; Lapadula, Pavoletti
Cremonese possible starting lineup:
Jungdal; Antov, Lochoshvili, Bianchetti; Barbieri, Pickel, Castagnetti, Vendeputte, Quagliata; Johnson, De Luca
We say: Cagliari 1-0 Cremonese
It may be a close contest between one team struggling in Serie A and another faring well in Italy's second tier, but Cagliari should come out on top and secure progress in the Coppa Italia.