The 26-year-old was withdrawn after 29 minutes of the goalless draw at Catania after complaining of sharp pain when planting his studs in the turf.
A statement on the club's official website read: "Francesco Pisano has suffered a fracture to the fibula of his left leg.
"The prognosis will be better defined over the next few days but it is clear that the season is already over for the defender."
The Sardinian right-back has been a near ever-present for Cagliari this season, making 28 league appearances as Ivo Pulga's men continue to establish themselves in mid-table.
He said: "I felt my foot twist when blocking an opponent who was going to shoot and felt a sharp pain. I knew immediately it was something serious."