His father Francesco Sfondrati, a senator of the ancient comune of Milan, after the death of his wife in 1538 entered in the ecclesiastic state and was created cardinal-priest by Pope Paul III in 1544.

Returned in his diocese, he applied the reforms of the Council of Trent under the supervision of his Metropolitan Archbishop, Cardinal Charles Borromeo, to whom he was related.

After the death of Pope Urban VII on 27 September 1590, the Spanish ambassador Olivares presented the conclave a list of the seven cardinals who would be acceptable to his master Philip II of Spain.

Cardinal Alessandro Peretti di Montalto came to Sfondrati's cell to inform him that the Sacred College had agreed on his election and found him kneeling in prayer before a crucifix.

"[8] In his bull of 21 March 1591, Cogit nos, he forbade under pain of excommunication all betting concerning the election of a Pope, the duration of a pontificate, or the creation of new cardinals.

Gregory XIV, who was in poor health before his election to the papacy, died due to a large gallstone and was succeeded by Innocent IX.