When one of the Gobugyo (five major magistrates), Mitsunari ISHIDA, rose in arms during their absence and caused the Battle of Sekigahara, he backed up the Western Camp with his father, parting ways with his older brother Nobuyuki SANADA, who sided with the Eastern Camp because his wife (Komatsuhime) was a daughter of Tadakatsu HONDA.
留守中に五奉行の石田三成らが挙兵して関ヶ原の戦いに至ると、父と共に西軍に加勢し、妻が本多忠勝の娘（小松姫）で徳川方の東軍についた兄・真田信之と袂を分かつことになる。