Abby Walker's husband is murdered before her eyes. On her quest for revenge, Abby crosses paths with Hoyt Rawlins. Abby and Hoyt's journey takes them to Independence, Texas, where they encounter residents running from their own pasts.

Com base em acontecimentos verídicos, A Senhora de Guadalupe é uma descoberta religiosa comovente que justapõe o folclore com os tempos modernos.