Background: Studies have shown that mini-alpha A can protect retinal pigment epithelium (RPE) cells from apoptosis. However, no in vivo study concerning the anti-apoptotic function of mini-alpha A has been conducted yet. Methods: MTT assay, HE staining and TUNEL assay were used to assess levels of cells, and an animal model was established to examine the protective effects of mini-alpha A against NaIO3-induced RPE cell apoptosis. Western blot analysis and RT-qPCR were performed to explore the possible mechanism of mini-alpha A's protective function against NaIO3-induced RPE cell apoptosis. Results: Results from in vivo and animal experiments showed that mini-alpha A antagonized NaIO3-induced RPE cell apoptosis. Further investigation into how mini-alpha A provided protection against NaIO3-induced RPE cell apoptosis showed that mini-alpha A reduced NaIO3-induced RPE cell apoptosis and autophagy. In addition, unfolded protein response was also involved in the protective effects of mini-alpha A against NaIO3-induced RPE cell apoptosis. Conclusions: mini-alpha A can antagonize RPE cell apoptosis induced by NaIO3. A possible mechanism is by inhibition of apoptosis by repressing autophagy and endoplasmic reticulum stress.