Troops taking Ferrara's side, loosely under the command of Federico da Montefeltro, duke of Urbino, are those of Ercole's father-in-law Ferdinand of Naples, under his son Alfonso of Calabria, who invaded the Papal States from the south, as well as those sent by Ludovico il Moro of Milan and by the lords of two cities threatened by the mainland power of Venice, Federico I Gonzaga of Mantua and Giovanni II Bentivoglio of Bologna.

Venetian troops led by the condottiero Roberto Sanseverino attack Ferrarese territory from the north, brutally sacking Adria, quickly overrunning Comacchio, attacking Argenta at the edge of the saltmarshes and besieging Ficarolo in May, which capitulates on June 29, and Rovigo, which capitulates on August 17.

Venetian forces cross the Po River and in November 1482 stand before the walls of Ferrara and lay strict siege to the city.

Sixtus appears to have had a change of heart at the season's advances, which now threaten o put Venice in an uncomfortably strong position in mainland northern Italy.