This study investigates the neuroprotective effects of salidroside (SAL) on Parkinson's Disease (PD) by focusing on the modulation of the Nuclear Factor E2-Related Factor 2 (Nrf2)/Glutathione Peroxidase 4 (GPX4) pathway. In vivo, male C57BL/6 mice were induced with PD-like symptoms using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and treated with SAL or a Nrf2 inhibitor. Behavioral tests, immunohistochemical staining, transmission electron microscopy, and Western blot analysis were conducted to assess motor functions, pathological changes, ferroptosis, and related protein expressions. In vitro, SH-SY5Y cells were treated with erastin to induce ferroptosis, and the protective effects of SAL were evaluated. Additionally, A53T-α-syn-overexpressing cells were used to elucidate the role of the Nrf2/GPX4 pathway in mitigating ferroptosis. The results showed that SAL significantly improved motor functions, reduced α-syn expression, and increased tyrosine hydroxylase (TH) expression in PD mice. In vitro, SAL increased TH, GPX4, and Nrf2 expression and mitochondrial membrane potential while alleviating ferroptosis through the Nrf2/GPX4 pathway. These effects were reversed by Nrf2 inhibition. The study concludes that SAL demonstrates significant potential in mitigating PD pathology and ferroptosis, positioning the Nrf2/GPX4 pathway as a promising therapeutic target. However, future studies should focus on the long-term effects, pharmacokinetics, and multifactorial nature of PD pathogenesis.This study investigates the neuroprotective effects of salidroside (SAL) on Parkinson's Disease (PD) by focusing on the modulation of the Nuclear Factor E2-Related Factor 2 (Nrf2)/Glutathione Peroxidase 4 (GPX4) pathway. In vivo, male C57BL/6 mice were induced with PD-like symptoms using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and treated with SAL or a Nrf2 inhibitor. Behavioral tests, immunohistochemical staining, transmission electron microscopy, and Western blot analysis were conducted to assess motor functions, pathological changes, ferroptosis, and related protein expressions. In vitro, SH-SY5Y cells were treated with erastin to induce ferroptosis, and the protective effects of SAL were evaluated. Additionally, A53T-α-syn-overexpressing cells were used to elucidate the role of the Nrf2/GPX4 pathway in mitigating ferroptosis. The results showed that SAL significantly improved motor functions, reduced α-syn expression, and increased tyrosine hydroxylase (TH) expression in PD mice. In vitro, SAL increased TH, GPX4, and Nrf2 expression and mitochondrial membrane potential while alleviating ferroptosis through the Nrf2/GPX4 pathway. These effects were reversed by Nrf2 inhibition. The study concludes that SAL demonstrates significant potential in mitigating PD pathology and ferroptosis, positioning the Nrf2/GPX4 pathway as a promising therapeutic target. However, future studies should focus on the long-term effects, pharmacokinetics, and multifactorial nature of PD pathogenesis.