Oxidative stress, which damages cellular components and causes mitochondrial dysfunction, occurs in a variety of human diseases, including neurological disorders. The clearance of damaged mitochondria via mitophagy maintains the normal function of mitochondria and facilitates cell survival. Astaxanthin is an antioxidant known to have neuroprotective effects, but the underlying mechanisms remain unclear. This study demonstrated that astaxanthin inhibited HO-induced apoptosis in SH-SY5Y cells by ameliorating mitochondrial damage and enhancing cell survival. HO treatment significantly reduced the levels of activated Akt and mTOR and induced mitophagy, while pretreatment with astaxanthin prevented HO-induced inhibition of Akt and mTOR and attenuated HO-induced mitophagy. Moreover, the inhibition of Akt attenuated the protective effect of astaxanthin against HO-induced cytotoxicity. Taken together, astaxanthin might inhibit HO-induced apoptosis by protecting mitochondrial function and reducing mitophagy. The results also indicate that the Akt/mTOR signaling pathway was critical for the protection of astaxanthin against HO-induced cytotoxicity. The results from the present study suggest that astaxanthin can reduce neuronal oxidative injury and may have the potential to be used for preventing neurotoxicity associated with neurodegenerative diseases.