Caterina served as Regent of Milan from 1402 to 1404, during her elder son's minority, but due to Gian Maria's suspicion of her alleged treason (planted in his mind by her enemy, the condottiero Facino Cane), he had his mother arrested and imprisoned in the castle of Monza, where she was presumably poisoned in 1404.

Following the murder of her maternal grandfather, Isabeau became one of the most implacable enemies of Caterina's husband Gian Galeazzo and his daughter, Valentina, Duchess of Orleans.

To commemorate the event, a missal was painted by Anovelo da Imbonate, depicting, in the foreground, the kneeling figures of Caterina and Gian Galeazzo.

The Duchy was riven by strife and numerous revolts as rival factions between Gian Galeazzo's legitimate and illegitimate heirs contested for land and power during her regency.

Convinced of his mother's treachery, Gian Maria had Caterina arrested on 18 August 1404 and imprisoned in her own castle of Monza, where she died on 17 October 1404, allegedly of poisoning.