BACKGROUND: Parkinson's disease (PD) is characterized by progressive dopaminergic neuronal loss, and current treatments are limited by their inability to prevent neurodegeneration. NURR1, a crucial transcription factor for dopaminergic neuron survival, has emerged as a promising therapeutic target. This study investigated whether Saikosaponin A (SSA), a bioactive compound from Bupleuri radix, exhibits neuroprotective effects through NURR1-mediated mechanisms in 6-hydroxydopamine (6-OHDA)-induced PD models. METHODS: Cell viability assays, protein expression analysis, behavioral tests, and immunohistochemistry assessed SSA effects. PC12 cells were treated with SSA (0.1-20 µM) followed by 6-OHDA (75 µM) exposure. 6-OHDA-lesioned mice received SSA (5 mg/kg, po) for 10 days. Behavioral assessment included rotarod, pole, and apomorphine-induced rotation tests. Dopaminergic neuronal protection was evaluated through tyrosine hydroxylase (TH) immunohistochemistry and NURR1 expression analysis. RESULTS: In PC12 cells, SSA (10 µM) significantly restored NURR1 and tyrosine hydroxylase (TH) expressions compared to 6-OHDA group, while improving cell viability and antioxidative enzyme heme oxygenase-1 levels. SSA also enhanced cell survival signaling as evidenced by increased Bcl-2/Bax ratio. In 6-OHDA-lesioned mice, SSA treatment (5 mg/kg, po) significantly improved motor function in rotarod and pole tests, while reducing apomorphine-induced rotations. Furthermore, SSA protected TH-positive neurons in the substantia nigra and increased NURR1 expression compared to the 6-OHDA group. CONCLUSIONS: SSA demonstrates potential as a therapeutic agent for PD by modulating neuroprotective pathways associated with NURR1 expression. SSA provides dual benefits of motor function improvement and neuroprotection against dopaminergic neuronal death, representing a promising alternative to current symptomatic treatments that cannot halt disease progression.