<p>The NLRP3 inflammasome signaling cascade activation is a significant contributor to the initiation and progression of Parkinson’s disease (PD). Recent evidence supports that targeting NLRP3 inflammasome assembly could be a potential strategy to halt PD progression. The molecular mechanism of the olfactory-brain axis in mediating PD remains elusive. The current study explores that MPTP exposure to C57BL/6 mice leads to glial cell activation and impairs the olfactory function. The role of NLRP3 inflammasome activation in the olfactory bulb and the brain mediating neuroinflammation and neurodegeneration by activating multiple inflammatory pathways is explored. Loganic acid (LA), an iridoid glycoside, has been shown to provide antioxidant, anti-inflammatory, and inhibit microglial activation. Our results in-vitro&#xa0;studies demonstrated that LA treatment in MPP⁺-induced microglial cells inhibits NLRP3 inflammasome assembly, halts phagocytosis, and downregulates the release of pro-inflammatory cytokines such as IL-1β and IL-18. Further, results confirm that LA increases the neuronal differentiation markers and assists neurite growth. To correlate the in-vitro experiments with the in-vivo study, LA treatment prevented the loss of olfactory and motor function. In immunoblotting, LA treatment significantly inhibits the expression of NLRP3 inflammasome signaling cascade when compared to the MPTP group of the olfactory bulb and substantia nigra. Computational studies on LA on IL-β, NLRP3, caspase-1, and ASC also support strong evidence in the downregulation of inflammasome and cytokines through potential non-covalent interactions. The results confirm the neuroprotective effect of LA in PD by halting the NLRP3 inflammasome activation in the olfactory bulb and nigra region of the mice.&#xa0;</p> Graphical Abstract <p>Pathway depicting the molecular mechanism of MPTP in mediating the olfactory-brain axis dysfunction and the therapeutic effect of LA in restoring neuroinflammation and neurodegeneration.</p> <p></p>