Defeat to Juventus on Sunday leaves the hosts seventh in Serie A, with their fellow Emilian side currently occupying a playoff place in the second tier.
Neither of these two relatively modest clubs have ever lifted the Coppa Italia in several decades of trying - with most of their time spent in their lower echelons of Italian football - and will now go head-to-head for the chance to face Juventus or Genoa in the last eight later this month.
Sassuolo come into a tie they will be expected to win - given their current status as overachieving dark horses in the top flight - on the back of a defeat to Scudetto-holders Juventus last weekend.
Despite that 3-1 loss in Turin, after being reduced to ten men at the end of the first half, Roberto De Zerbi's team are once again enjoying a decidedly positive season in Serie A.
Unburdened by many midweek fixtures - as they did not qualify for European competition but finished high enough last term to earn a free pass to this stage in the Coppa - the Neroverdi have continued to impress and succumbed to Juve's pressure only in the final minutes on Sunday.
Still very much in the race for a European spot this season, Sassuolo reflect the philosophy of highly-rated head coach De Zerbi - with a distinct commitment to attack. By way of evidence, they have already racked up 30 league goals, with 26 conceded.
Their Mapei Stadium - set to host the Supercoppa Italiana between Juventus and Napoli next week - has been something of a Neroverdi stronghold, as in eight games there so far, they have lost only twice against title-chasing Inter Milan and AC Milan.
SPAL's rebound from finishing last in Serie A at the end of a difficult 2019-20 campaign has been commendable, as the Biancazzurri are in the mix for promotion straight back from Serie B.
An experienced squad, featuring top division stalwarts Sergio Floccari and Alberto Paloschi, has been peppered with borrowed talents such as Inter tyro Sebastiano Esposito and Fiorentina's Luca Ranieri.
Former Udinese coach Pasquale Marino led his side to success in their most recent league outing against Frosinone. That 2-1 win was their last fixture before the cup tie in Sassuolo, as the Italian second tier will not resume until the weekend, after ten days of inactivity.
Once Coppa runners-up in 1962, the Ferrarese began their journey to the final 16 at the end of September - eliminating Bari and Crotone (both on penalties) and then moneyed Monza in the previous rounds.
Marino now prepares his team, who naturally lost several stars such as Mohamed Fares (to Lazio), Arkadiusz Reca (Crotone) and Andrea Petagna (Napoli) in the summer, for a significant challenge against one of the most progressive sides currently in Calcio.
Having never met in the Coppa Italia, the two clubs' last league encounter was in February 2020, when SPAL lost 2-1 at Stadio Paolo Mazza, and it will take a Herculean effort to pull off a different result on this occasion.
Sassuolo form (all competitions): DLWLWL
SPAL Coppa Italia form: DDW
SPAL form (all competitions): DDWLLW
Roberto De Zerbi will again be without striker Domenico Berardi due to a thigh injury, as well as long-term absentee Filippo Romagna and winger Federico Ricci - who is close to signing for Monza. Midfielder Mehdi Bourabia was omitted against Juventus, as he has also been linked with a move away from the club.
Likely to rotate some of his first XI, De Zerbi may promote goalkeeper Gianluca Pegolo to the starting lineup, with a well-earned rest possible for Manuel Locatelli in midfield. He would be replaced by veteran Francesco Magnanelli or Pedro Obiang, who is suspended for the forthcoming league visit of Parma after his reckless red card last Sunday.
If Francesco Caputo is also given a break, Nicolas Schiappacasse, Hamed Traore and Lukas Haraslin are likely to start in support of Giacomo Raspadori, with weekend goalscorer Gregoire Defrel also in contention for a forward spot.
SPAL boss Pasquale Marino could welcome back Albania goalkeeper Etrit Berisha in this fixture, as he has resumed training after recovering from hospitalisation due to COVID-19. More probably though, Senegalese stopper Demba Thiam will continue between the posts.
Midfielder Lucas Castro may not be available due to a knee injury, with Gabriel Strefezza and Salvatore Esposito favoured to start. Winger Enrico Brignola, on loan from Sassuolo, and talented trequartista Mattia Valoti should play behind Sergio Floccari up front.
Sassuolo possible starting lineup:
Pegolo; Toljan, Ayhan, Marlon, Kyriakopoulos; Magnanelli, Obiang; Schiappacasse, Traore, Haraslin; Raspadori
SPAL possible starting lineup:
Thiam; Sernicola, Vicari, Ranieri; Strefezza, Esposito, Missiroli, Sala, Brignola; Valoti; Floccari
We say: Sassuolo 2-1 SPAL
Though their squad does not run particularly deep, Sassuolo should have enough in reserve to make changes but still see off the challenge of their fellow Emilians on Thursday.
Sparsely-used forwards such as the experienced Gregoire Defrel and young Giacomo Raspadori are equipped with the nous to breach SPAL's defence on at least one occasion, with Roberto De Zerbi's side still tuned to the only frequency they know - attack.