Background: Parkinson’s disease (PD) continues to be a neurological challenge with limited therapeutic options. This study aimed to investigate the potential therapeutic effects of GM3 ganglioside, focusing on its role in mitigating LPS-induced parkinsonism behaviors, gliosis, and neurotoxicity. Methods: We employed a range of in vivo tests, including rotarod and beam-walking, to assess motor function improvements in LPS-induced parkinsonism following GM3 ganglioside pre-treatment. Dopaminergic neurotoxicity was examined using [18F]FE-PE2I PET imaging and TH staining of the striatum. Further, we investigated the impact of GM3 ganglioside on LPS-induced gliosis by observing changes in microglial activation and astrocytic proliferation. Results: Pre-treatment with GM3 ganglioside significantly improved motor functions, as evidenced by enhanced performance in rotarod and beam-walking tests. Our findings also showcased GM3 ganglioside’s efficacy in countering LPS-induced dopaminergic neurotoxicity, with [18F]FE-PE2I PET imaging and TH staining supporting its neuroprotective potential. Importantly, GM3 ganglioside pre-treatment notably reduced LPS-induced gliosis, demonstrating a significant decrease in both microglial activation and astrocytic proliferation. Conclusions: GM3 ganglioside presents promising neuroprotective capabilities, effectively mitigating LPS-induced parkinsonism behaviors and gliosis. These findings underscore GM3 ganglioside’s potential as a valuable therapeutic avenue for future Parkinson’s disease interventions.