Parkinson’s disease (PD), a debilitating neurodegenerative disorder, is primarily characterized by motor impairments and concurrent gastrointestinal disturbances. Increasing evidence has highlighted the critical role of the microbiota–gut–brain axis (MGBA) in the pathogenesis of PD. This study investigated the neuroprotective potential of sodium hyaluronate (SH) in a mouse model of PD and its underlying mechanisms via the MGBA. In the oral pre-treatment study, three doses (7.5, 15, and 30 mg/kg/day) were evaluated. The results showed that the high dose (SH-H, 30 mg/kg/day) significantly ameliorated motor disorders and gastrointestinal functional disorders. Therefore, SH-H was selected for subsequent mechanistic investigations. Mechanistically, SH-H restored gut microbiota homeostasis, increased fecal short-chain fatty acid (SCFA) levels, and improved the integrity of the intestinal and blood–brain barrier (BBB). Thus, SH reduced the transfer of lipopolysaccharide (LPS) from the intestine to serum and the substantia nigra (SN), suppressing activation of the LPS-TLR4/MyD88/NF-κB signaling pathway. These effects alleviated neuroinflammation, protected dopaminergic neurons, and reduced the aggregation of α-synuclein (α-syn). In summary, SH attenuated PD-related pathological changes by restoring gut microbiota homeostasis and modulating the MGBA, suggesting that SH may represent a potential therapeutic strategy for PD.