While the hosts were swept aside by Juventus on Monday, their southern counterparts returned to the top flight by narrowly missing out on a point against Inter.
Match preview
Having won only once before away to Juventus - though that victory came as recently as last October - Sassuolo were always outsiders to kick off the new Serie A season successfully.
Indeed, the Neroverdi lost their eighth of 10 fixtures in Turin against their hosts on Monday night, as they were dealt a 3-0 defeat at the Allianz Stadium, with Juve inspired by star signing Angel Di Maria, who produced a goal and an assist on his debut.
Though the scoreline was perhaps a little harsh on Sassuolo, they failed to find the net having lost Gianluca Scamacca to West Ham United and with his fellow Italy international Giacomo Raspadori consigned to the bench until the second half, as he closes in on a potential move to Napoli.
Such disruption to his previously potent forward line, meant Alessio Dionisi had to improvise up front, and the pressure is on the Neroverdi coach to rebuild rapidly and integrate recent arrivals, including Andrea Pinamonti from Inter.
After a number of top-half finishes, the Emilians slipped to 11th in Dionisi's first season at the club since succeeding Roberto De Zerbi, and as Sassuolo also slumped out of the Coppa Italia earlier this month - losing 3-2 at Serie B side Modena - they will be even more keen to beat promoted opponents this weekend.
After weeks of hope and anticipation, Lecce endured a nightmare start to their Serie A return on the opening day, as Romelu Lukaku breached their defence less than two minutes into Inter's visit to Stadio Via del Mare.
Assan Ceesay's strike just after half-time brought the Giallorossi back level, but over 90 minutes after Lukaku's opener, Denzel Dumfries stole all three points for the visitors with a stoppage-time winner from close range.
Lecce have played the most matches in Serie A opening rounds without posting a single win - 17 in all, while losing each of their last six - so while the manner of their defeat will have stung, few would have expected the Puglian side to topple one of Calcio's giants.
Last season's Serie B champions, who returned to Italy's top tier at the second attempt, now approach their first road trip of the new season following a run of three straight defeats.
As Marco Baroni's young side ended their pre-season programme with a loss to Parma, before crashing out of the Coppa Italia to Cittadella - by whom they were beaten 3-2 in extra time - they may find the going tough at the Mapei Stadium.
Sassuolo Serie A form:
Sassuolo form (all competitions):
Lecce Serie A form:
Lecce form (all competitions):
Team News
While Alessio Dionisi will still be without Ivorian winger Hamed Traore due to a foot injury, the Sassuolo coach can now call upon midfield mainstay Maxime Lopez, who returns from suspension and should start.
After another summer of speculation, long-serving captain Domenico Berardi (15 goals and 14 assists in Serie A last season) remains at the club, and renewed his commitment by signing a fresh five-year deal this week.
The Italy forward is joined up front by either Gregoire Defrel, Agustin Alvarez or Andrea Pinamonti, one of whom will lead an attacking trio in which left-back Giorgios Kyriakopoulos was pressed into service on Monday - Giacomo Raspadori was restricted to a substitute role in Turin, as his time at the club apparently nears an end.
Lecce, meanwhile, have an almost fully fit squad for the trip to Emilia-Romagna, though Marco Baroni has concerns about the fitness of defensive pair Kastriot Dermaku and Mert Cetin - the latter limped off after only 21 minutes against Inter last week.
Former France Under-21 international Alexis Blin is favourite to step into the back four of Baroni's attack-minded 4-3-3 formation.
Several summer signings made their debut on the opening day, including Milan loanee Lorenzo Colombo and goalkeeper Wladimiro Falcone, but Norwegian midfielder Mathias Normann will not be joining them in the visitors' squad, after his move from Rostov was ended only hours after its confirmation.
Sassuolo possible starting lineup:
Consigli; Muldur, Erlic, Ferrari, Kyriakopoulos; Lopez, Frattesi, Thorstvedt; Berardi, Pinamonti, Ceide
Lecce possible starting lineup:
Falcone; Gendrey, Blin, Baschirotto, Gallo; Bistrovic, Hjulmand, Askildsen; Strefezza, Ceesay, Di Francesco