Sophora species are used as dietary medicines in aging-associated symptoms. Sophora tomentosa L. (ST) is a native medicinal plant in Southeast Asia; however, there is no pharmacological literature about ST extract. The present study evaluates the antioxidant phytoconstituent contents and radical scavenging capacities of ST extract. The further investigation was to clarify the neuroprotective mechanism of ST extract against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinsonism by assaying the activities of the dopaminergic system and antioxidant defenses, glycogen synthase kinase 3β (GSK3-β) phosphorylation, and α-synuclein levels in C57BL/6 mice. The results show that ST extract alleviated the motor deficits in MPTP-induced Parkinsonism with four behavioral tests, including a rearing locomotor, catalepsy test, balance beam walking test, and pole test. ST extract reversed the number of tyrosine hydroxylase (TH)-positive neurons in substantia nigra (SN) that had decreased by MPTP. ST extract also restored the decreased levels of dopamine and the expression of tyrosine hydroxylase (TH) in the striatum. Furthermore, ST extract restored the levels of glutathione (GSH) and the activities of antioxidant enzymes, and decreased the elevated levels of malondialdehyde (MDA) in mouse striatum. ST extract also decreased α-synuclein overexpression and GSK-3β phosphorylation in mouse striatum. In vitro, ST extract exerted higher 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical scavenging capacities through its higher phenolic contents, especially protocatechuic acid and epicatechin. These results suggest that ST extract has the potential to counteract MPTP-induced motor deficit. The neuroprotective mechanism of ST extract against MPTP-induced Parkinsonism might be related to decreasing GSK-3β phosphorylation and restoring the activities of striatal antioxidant defenses to restore the nigrostriatal dopaminergic function and decrease α-synuclein accumulation.