Cadmium (Cd) is a widespread environment contaminant due to the development of electroplating and metallurgical industry. Cd can be enriched by organisms via food chain, causing the enlarged environmental problems and posing threats to the health of humans. Polydatin (PD), a natural stilbenoid compound derived from Polygonum cuspidatum, shows pronouncedly curative effect on oxidative damage. In this work, the protective effects of PD on oxidative damage induced by Cd in Musca domestica (housefly) larvae were evaluated. The larvae were exposed to Cd and/or PD, subsequently, the oxidative stress status, mitochondria activity, oxidative phosphorylation efficiency, and survival rate were assessed. Cd exposure generated significant increases of malondialdehyde (MDA), reactive oxygen species (ROS) and 8-hydroxy-2-deoxyguanosine (8-oxoG) in the housefly larvae, causing mitochondrial dysfunction and survival rate decline. Interestingly, pretreatment with PD exhibited obviously mitochondrial protective effects in the Cd-exposed larvae, as evidenced by reduced MDA, ROS and 8-oxoG levels, and increased activities of superoxide dismutase (SOD), mitochondrial electron transfer chain, and mitochondrial membrane potential, as well as respiratory control ratio. These results suggested that PD could attenuate Cd-induced damage via maintaining redox balance, stimulating SOD activity, and regulating mitochondria activity in housefly larvae. As a natural polyphenolic chemical, PD can act as a potential candidate compounds to relieve Cd injury.