Meanwhile, Crotone are playing their first home fixture in Serie A since 2018 after earning promotion from the second tier.
After a strong finish to last season, Stefano Pioli is under pressure to turn AC Milan into Serie A title challengers over the course of this campaign.
A 2-0 victory over Bologna on Monday evening courtesy of a Zlatan Ibrahimovic double represented the perfect start for the Italian giants.
However, with their star man having tested positive for coronavirus and a less-than-convincing showing being produced against Bodo/Glimt in the Europa League, there is much work ahead for this team.
I Rosseneri have put together a 16-match unbeaten streak in all competitions, a run which has included 12 wins, but Pioli will be eager to quickly extend that to 19 fixtures before the derby against Inter Milan.
As well as games against newly-promoted Crotone and Spezia, Milan travel to Portugal to take on Rio Ave for a place in the Europa League group stages.
From Crotone's perspective, this is one of the glamour fixtures which they have been anticipating since ending their two-season spell in Serie B.
Nevertheless, reality would have kicked in last weekend when they quickly found themselves two goals down at Genoa, eventually losing out 4-1 to opponents who narrowly avoided relegation as recently as July.
I Pitagorici had the consolation of getting on the scoresheet through the well-travelled Emmanuel Riviere, but they must improve defensively if they wish to avoid a season-long battle at the wrong end of the table.
With Sassuolo and Juventus to follow Sunday's fixture, boss Giovanni Stroppa will recognise that it may be a case of damage limitation over the coming weeks.
Crotone Serie A form: L
AC Milan Serie A form: W
AC Milan form (all competitions): WWW
With Ibrahimovic sidelined for at least the next two matches, Pioli must decide whether to hand a first league start to teenager Lorenzo Colombo.
Sandro Tonali may also be brought into the lineup for his first start since signing from Brescia.
With next Thursday's important clash against Rio Ave in mind, Pioli will give thought to making further alterations.
Crotone's Andrea Rispoli could be brought in a replacement for Antonio Mazzotta at wing-back.
After their improved second-half showing against Genoa, that may prove to be the only alternation.
Crotone possible starting lineup:
Cordaz; Magallan, Marrone, Golemic; Molina, Cigarini, Zanellato, Rispoli; Messias; Simy, Riviere
AC Milan possible starting lineup:
Donnarumma; Calabria, Kjaer, Gabbia, Hernandez; Tonali, Bennacer; Castillejo, Calhanoglu, Rebic; Colombo
We say: Crotone 1-4 AC Milan
Given the size of their defeat last weekend, this is not the ideal second fixture for the newcomers. Although Milan were far from convincing in the Europa League, we expect the visitors to cruise to victory at the weekend.