In this work, we demonstrate that a delayed, post-injury administration of a clinically relevant dose of 17β-estradiol reduces secondary damage and promotes functional recovery after SCI. Specifically, we show that administration of either the 0.5- or 5.0-mg slow-release pellet: improves hindlimb locomotion, as evaluated with the BBB open-field score; increases white-matter sparing at the lesion epicenter; and increases neuronal survival in the ventral horn. Additionally, we found that post-SCI administration of 17β-estradiol significantly decreases apoptosis in the ventral horn and favorably modulates the ratio of pro- and anti-apoptotic Bcl-2 family proteins. We also show that eliminating testicular-derived androgens significantly increases apoptosis but does not alter the protective effect of 17β-estradiol on apoptotic cell death, which suggests that testosterone and 17β-estradiol may act by separate mechanisms to reduce apoptosis after SCI.