Toll-like receptors (TLRs) belong to a pattern recognition receptor class which is an integral part of innate immunity. During Parkinson’s disease (PD), activation of the immune response is a well-established feature in both, the periphery and the brain. The role of TLR is considered to be a salient part of the established framework during inflammation and neurodegenerative disease such as PD. The link between inflammation-mediated TLR expression and the molecular hallmark of PD pathogenesis is well established. Various evidence in support of the review has proved the presence of α-synuclein-positive inclusions, inciting the activated microglia to promote the expression of microglial and neuronal TLRs. Thus, the long-established inflammatory environment is considered as the pivotal element in the progression of the PD pathology. This review aims to delineate the importance of TLRs (TLR2/4) and their altered signaling in the pathogenesis of PD via cascade of proinflammatory pathways and the new therapeutic propositions to modulate the TLR expression. The microglia-mediated inflammatory pathway and aggregated α-synuclein potentiates multiple mechanisms through which inflammation contributes to progression of neurodegeneration in PD via upregulation of TLR2 and TLR4. TLR targeting is a site of interest to facilitate effective treatment for PD.