Objective  To explore the neuroprotective effects and mechanisms of the sesquiterpene lactone compound ACT001 on rotenone (ROT) -induced Parkinson’s disease (PD) model mouse.  Methods  SPF C57BL/6 mice were randomly divided into 6 groups, including control group, solvent control group, ROT model group, ACT001 5 mg/kg group（ROT+ACT001-5）, ACT001 20 mg/kg group（ROT+ACT001-20）, and levodopa(L-dopa) positive control group(ROT+L-dopa)，with 9 mice in each group. The control group received an equivalent amount of intraperitoneal injection of saline, the solvent control group received an equivalent amount of rotenone solvent without rotenone, the remaining groups of mice were used to establish a PD mouse model by intraperitoneal injection of rotenone. Mice in different ACT001 dosage groups received intraperitoneal injections of high and low doses of ACT001, while the positive control group received levodopa intraperitoneally for 15 consecutive days. Behavioral changes in mice were assessed using open field, rotarod, pole-climbing, and balance beam tests. Immunofluorescence (IF) assay to detect the expression of tyrosine hydroxylase (TH) neurons，content of TH-positive fibers in the striatum and to detect the activation status of nigrostriatal microglia in the mouse midbrain; Real-time PCR was employed to measure the levels of interleukin (IL)-6, IL-1β, and tumor necrosis factor-α (TNF-α) in the substantia nigra of the mouse brain. Western blotting was used to measure the protein levels of TH, nuclear factor-κB (NF-κB) p65, NF-κB inhibitor α (IκBα), and phosphorylated IκBα (p-IκBα) in the substantia nigra of the mouse brain.  Results  Compared to the control group and the solvent control group, the rotenone-induced PD model group exhibited motor impairments in behavioral tests, a decrease in the number of TH positive neurons in the substantia nigra (P <0.0001), decreased levels of TH-positive fibers in the striatum, activation of midbrain substantia microglia，and elevated levels of IL-6,  IL-1β, TNF-α, p-IκBα, and NF-κB p65 expression. ACT001 significantly improved the behavioral impairments and substantia nigra damage in PD mice, increased the number of TH-positive neurons in the substantia nigra, increased levels of TH-positive fibers in the striatum, inhibition of microglial cell activation in the midbrain substantia nigra, and elevated the protein expression levels of IκBα while reducing the levels of IL-6, IL-1β, TNFα, -IκBα, and NF-κB p65 in the substantia nigra ( P<0.05). At a dose of 5 mg/kg, ACT001 significantly improved behavioral impairments in rotenone-induced PD mice, reduced the loss of dopaminergic neurons, and its mechanism may be related to the inhibition of the NF-κB  signaling pathway and the suppression of inflammation. In summary, the intervention of ACT001 in the rotenone-induced PD mouse model inhibited the inflammatory response in the midbrain, increased the number of TH-positive neurons, and augmented the population of dopaminergic neurons in the substantia nigra, exerting a protective effect on neurons.   Conclusion  ACT001 significantly improves behavioral deficits in ROT-induced PD mice, ameliorates of dopaminergic neuron loss from the midbrain substantia nigra and striatum, inhibits the activation of nigrostriatal microglia in the midbrain, and suppresses inflammatory responses by inhibiting the activation of the NF-κB signaling pathway.