The hosts enter the competition at this stage due to their impressive league finish last term and will vie with their Sardinian visitors for the right to meet Sampdoria or Juventus in the quarter-finals.
Having started the year with four points from a possible six against teams from the bottom half of the Serie A standings, Sassuolo saw their progress derailed on Sunday by a careless performance versus Verona.
Though the Neroverdi managed to score twice themselves, through Gianluca Scamacca's close-range volley and a header from substitute Gregoire Defrel, they came a cropper at their Reggio-Emilia headquarters - conceding an Antonin Barak hat-trick in a 4-2 defeat.
Alessio Dionisi's side did pull within a goal of their opponents early in the second half, but centre-back Vlad Chiriches then gave away a penalty which Barak coolly converted, making it 16 successive games that they have now conceded in Serie A.
Nonetheless, they have lost only two of their last 10 league outings, and the ex-Empoli coach had previously masterminded a 5-1 victory over his former club on away soil, with his talented attacking trident picking apart the Tuscan team's defence.
Giacomo Raspadori, Scamacca and their fellow Italy international Domenico Berardi - who was sorely missed on Sunday - all found the net at the Castellani, and the latter pair were also on target when Sassuolo drew 2-2 with this week's Coppa Italia opponents in November.
Held at the Mapei Stadium that day by a side which has struggled to pick up points in the league, the Emilians will now aim for a better result at the same venue as they switch attention to their cup campaign - having never lifted the trophy before in their history.
Cagliari have also failed to upset the odds and claim the Coppa, though they did once reach the final in 1969, when they were beaten by capital heavyweights Roma.
The same opposition sent the Isolani to defeat on Sunday evening too, as they were edged out 1-0 at Stadio Olimpico - being denied an equaliser by the crossbar in the closing minutes.
Nevertheless, Walter Mazzarri's men had come from behind to win both of their previous two league games - lifting themselves back into the mix for Serie A survival after a terrible start to the campaign - and will now be able to play free of expectation in cup competition.
The Rossoblu reached this stage by virtue of 3-1 victories against Serie B sides Pisa and Cittadella, in August and December respectively. To progress to the quarter-finals, though, they will have to rise above their general malaise on the road, having picked up three draws and just one win from their 11 away games this season.
Sassuolo will have their talisman Domenico Berardi back in the fold on Wednesday, as he returns from serving a suspension in Serie A, but several other players, including Filip Djuricic, Hamed Traore and Henrique, are unavailable to Alessio Dionisi.
The Neroverdi coach criticised midfielder Maxime Lopez for his first-half performance in the loss to Verona, calling his attitude into question, so the Frenchman may be among those rotated out of the side as the hosts make some changes - in particular, Kaan Ayhan and Abdou Harroui are both pushing for a place.
Both Giacomo Raspadori and Gianluca Scamacca have scored five times for the club since the start of December, and may join Berardi in a three-man attack, but Dionisi could well offer Gregoire Defrel a start instead.
Meanwhile, Cagliari still have Kevin Strootman, Martin Caceres and Sebastian Walukiewicz ruled out by injury, while Matteo Lovato - on loan from Atalanta until the end of the season - is a minor doubt, and Keita Balde remains on Senegal duty at the Africa Nations Cup.
Walter Mazzarri is likely to rotate his wing-backs, bringing Raoul Bellanova and Charalampos Lykogiannis in for Gabriele Zappa and Dalbert respectively, and back-up goalkeeper Boris Radunovic may be given a chance to impress between the posts.
Sassuolo possible starting lineup:
Pegolo; Toljan, Ayhan, Ferrari, Rogerio; Frattesi, Harroui; Defrel, Raspadori, Kyriakopoulos; Scamacca
Cagliari possible starting lineup:
Radunovic; Altare, Lovato, Carboni; Bellanova, Nandez, Grassi, Pereiro, Lykogiannis; Pedro, Pavoletti
We say: Sassuolo 2-0 Cagliari
With greater firepower and home advantage in their favour, Sassuolo should progress to the final eight and continue their pursuit of some rare silverware.
Even if the hosts decide to field an unfamiliar first XI, Cagliari are notoriously bad travellers and will inevitably be caught out defensively at some stage.
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