Sulfur mustard (SM) is a major toxic chemical threat to public health. Mitochondrial dysfunction is considered a critical contributing factor to mustard agent-induced damage. The brain is vulnerable to SM, which can lead to various types of acute and long-term psychiatric distress after exposure, but the neurotoxic mechanisms of SM, let alone drug candidates for antidotes, are seldom studied. In this study, we employed a library of mitochondrion-targeted compounds to screen for antidotes for SM-induced neurotoxicity. Our data revealed that dichloroacetate (DCA) noticeably reduced neuronal death and helped maintain the normal morphology and function of mitochondria both in vitro and in vivo. Further experiments revealed that DCA protected neurons by inhibiting pyruvate dehydrogenase kinase (PDK), thus upregulating pyruvate dehydrogenase (PDH) and activating the protein kinase B (Akt)/Nuclear factor-erythroid 2-related factor 2 (Nrf2) pathway. Overall, our results indicated that DCA could protect against SM-induced neurotoxicity through the PDK/PDH axis and the Akt/Nrf2 pathway, suggesting that DCA is a potentially novel antidote for SM poisoning.