Objective To investigate the effects of tetrahydroxy-stilbene glucoside (TSG) on the behavioral and pathological changes in A53T mutant α-synuclein (α-syn) transgenic mice. Methods Six months old A53T α-syn transgenic mice were divided into model group (Tg+ group)， model+ low dose group (50 mg/kg) and model+high dose group (100 mg/kg). Brood negative transgenic mice were divided into control group (Tg-) and high dose group (100 mg/kg). The administration groups were given TSG by gavage everyday for 9 months， while the control and model groups were given equal volume of distilled water. The movement abilities of mice were measured by pole test and nest building test. The immunohistochemical method was used to detect tyrosine hydroxylase (TH)-labeled neurons in the substantia nigra of mice. Results Compared to negative transgenic mice， the latency prolonged in pole test and the score of nest building were decreased， and the number of TH positive neurons were declined in substantia nigra compacta of A53T α-syn transgenic mice. Intragastrical administration of TSG for 9 months significantly shortened the latency in pole test， increased the score of nest building， and increased the number of TH positive neurons in substantia nigra compacta of α-syn transgenic mice. Conclusions TSG could obviously improve the motor function and increase the number of dopaminergic neurons in substantia nigra of A53T α-syn mice. It is suggested that TSG may be beneficial to the treatment of synuclein-related neurodegenerative diseases such as Parkinson disease.