In 1652, Ruxandra was married off to Tymofiy Khmelnytsky of the Cossack Hetmanate. Khmelnytsky's support was crucial in Moldavia's subsequent clash with Wallachia, but defeat in that conflict resulted in his death and in Lupu's dethronement. She opted to live in Cossack Podolia, at Rashkiv (Rașcov) and Yampil. She married a second time, to Andriy Antonovsky, a member of the Hetmanate's "starshyna"—when he died, Ruxandra came under the watch of her former brother-in-law, Yurii Khmelnytsky, who reportedly treated her as his hostage. In 1658, her half-brother, Ștefăniță Lupu, who had managed to obtain the Moldavian throne, besieged Rashkiv, hoping to kidnap Ruxandra.