Background/Objectives: Parkinson's disease (PD) currently lacks disease-modifying therapies. Available treatments offer only symptomatic relief and fail to halt progressive dopaminergic neuron loss. American ginseng (Panax quinquefolius L.) is a well-recognized functional food with documented neuroprotective properties, largely ascribed to its ginsenoside and polysaccharide fractions. However, its endogenous protein component, the American ginseng protein-enriched fraction (AGP), remains underexplored in the context of PD. This study aimed to investigate the neuroprotective effects of dietary AGP on PD and its association with the microbiota-gut-brain axis (MGBA). Methods: AGP was purified, structurally characterized, and then orally administered to male C57BL/6 mice with MPTP-induced PD for 28 days. Multi-omics analyses and Western blotting were employed to evaluate its efficacy and explore potential underlying mechanisms. Results: AGP treatment significantly improved motor function and place navigation performance in the Morris water maze, restored striatal dopamine levels, and reduced α-synuclein (α-Syn) aggregation in PD mice. In addition, AGP was associated with suppression of the TLR4/MyD88/NF-κB/ERK inflammatory pathway, the reshaping of the dysregulated gut microbiota composition, and the correction of metabolic disorders in the sphingolipid and arachidonic acid pathways. Conclusions: AGP was associated with significantly improved neuroprotective effects in PD mice, accompanied by concurrent modulations of the gut microbiota, metabolic profiles, and inflammatory signaling. These associations suggest potential MGBA involvement, although directionality requires further investigation. These findings support further investigation of AGP as a candidate dietary intervention for neurodegenerative diseases.
