Abstract: In this study,the SH-SY5Y cell model with Parkinson"s disease-like lesions was established by using rotenone,and the effect and mechanism of fibroblast growth factor 21 (FGF21) on the cell model were explored. Different concentrations of FGF21 were used to treat neuronal injury model induced by rotenone,and cell viabilities were detected by MTT assay. Effects of FGF21 and rotenone on the apoptotic levels of SH-SY5Y cells were analyzed by using Annexin V-FITC detection kit. Western blot was used to assess the effects of FGF21 and rotenone on the protein levels of tyrosine hydroxylase (TH) and α-synuclein (α-syn) in SH-SY5Y cells. Effects of FGF21 and rotenone on reactive oxygen species (ROS) levels in SH-SY5Y cells were tested using DCFH-DA fluorescent probe. The results showed that FGF21 could reduce the damage in SH-SY5Y cells induced by rotenone,inhibit cell apoptosis,alleviate the abnormalities of TH and α-syn in SH-SY5Y cells induced by rotenone and down-regulate the abnormal ROS levels in SH-SY5Y cells. The results suggested that FGF21 may attenuate rotenone-induced neuronal damage through regulation of oxidative stress.