A 90th minute Luka Jovic goal salvaged Milan a 2-2 draw at bottom-of-the-table Salernitana, leaving them 11 points adrift of Inter and seven off Juventus in second.
Their third place is now under serious threat.
Fourth-placed Bologna, who have lost just two games this season compared to Milan's four defeats, are now only two points behind, with Fiorentina a further point back.
Sassuolo arrive at the San Siro on Saturday, and while they may not be a side in the best of form right now, this season has proven they can mix it with the best of them.
A run of four games without a win, taking just one point in the process, leaves them in 15th place with 16 points from 17 games, and lie just three points above the relegation zone, but Milan would do well to look beyond these statistics.
Sassuolo have won just four league games, but two of those came against Juventus and Inter, the only defeats suffered by the top two, and the 2-1 win over the league leaders Inter came at the San Siro.
Manager Alessio Dionisi will hope to have Domenico Berardi back when they face Milan, after their leading scorer missed the 2-1 loss to Genoa last weekend through illness, but the Sassuolo coach's injury problems are nothing compared to Pioli's.
Since the beginning of the season Milan have had 30 different injuries, with 20 of those caused by muscle problems, numbers which have put the manager's preparations and training methods under scrutiny.
The latest out is defender Fikayo Tomori, injured during the draw with Salernitana, and with Milan already without Malick Thiaw and Pierre Kalulu at the back, the January transfer window may bring some relief for Pioli, if he is still in charge.
Pioli is now in his fifth season at the club, and while the Scudetto won in 2022, Milan's first league title in over a decade, has earned him a certain amount of credit with the owners, patience may run out, especially with the fans.
A Champions League exit, albeit in a tough group containing Paris St Germain, Borussia Dortmund and Newcastle United, certainly did not help his cause, and the fact that Milan already look out of the title race is a serious cause for concern.
According to Italian media reports, Antonio Conte could be the man to replace Pioli should the club decide to take action.
Inter have a four-point lead over Juventus at the top and on Friday they travel to face 13th-placed Genoa, who won at Sassuolo last weekend and held Juventus to a 1-1 draw the week before.
Juventus host Roma on Saturday, with Jose Mourinho's side now in sixth place after their 2-0 win over Napoli last weekend.
Napoli will look to bounce back when they welcome Monza on Friday, as Walter Mazzarri has now suffered five defeats in his eight games in all competitions since taking over from Rudi Garcia in November.
They will be without Victor Osimhen and Matteo Politano, both sent off against Roma.
Bologna aim to preserve their top-four place when they travel to take on Udinese on Saturday, a side with just one win all season and one point above the relegation zone, but they have recorded 11 draws.
