Neuroinflammation is one of the hallmarks contributing to Parkinson's Disease (PD) pathology, where microglial activation occurs as one of the earliest events, triggered by extracellular alpha synuclein (aSYN) binding to the CD36 receptor. Here, CD36-binding nanoparticles (NPs) containing synthetic tartaric acid-based amphiphilic polymers (AMs) were rationally designed to inhibit this aSYN-CD36 binding. In silico docking revealed that four AMs with varying alkyl side chain lengths presented differential levels of CD36 binding affinity and that an optimal alkyl chain length would promote the strongest inhibitory activity towards aSYN-CD36 interactions. In vitro competitive binding assays indicated that the inhibitory activity of AM-based NPs plateaued at intermediate side chain lengths of 12- and 18-carbons, supporting the in silico docking predictions. These 12- and 18-carbon length AM NPs also had significantly stronger effects on reducing aSYN internalization and inhibiting the production of the proinflammatory molecules TNF-α and nitric oxide from aSYN-challenged microglia. All four NPs modulated the gene expression of aSYN-challenged microglia, downregulating the expression of the proinflammatory genes TNF, IL-6, and IL-1β, and upregulating the expression of the anti-inflammatory genes TGF-β and Arg1. Overall, this work represents a novel polymeric nanotechnology platform that can be used to modulate aSYN-induced microglial activation in PD.