Illustrating the role of inhibiting TLR4/MyD88/NF-κB/NLRP3 and driving microglia polarization towards M2 in the neuroprotective and memory-improving effects of scoparone in OVX/D-Gal rats. Scoparone reduces OVX/D-Gal-induced Aβ aggregation and tau hyperphosphorylation. It exerts its anti-inflammatory and neuroprotective effects via inhibiting TLR4/MyD88/TRAF-6/TAK-1 pathway and consequently inhibits the downstream effectors, NF-κB and JNK. Moreover, inhibition of NF-κB by scoparone abrogates the NLRP3 inflammasome activation and in turn mitigates caspase-1 production and IL-1β/18 secretion. Further, scoparone-induced inhibition of NLRP3 suppresses the neurotoxic M1 while enhances the neuroprotective M2 activated microglia markers. These effects contribute to scoparone’s ability to reduce neuro-inflammation, neuronal degeneration, Aβ aggregation, and tau hyperphosphorylation. D-Gal D-galactose, OVX ovariectomy, Aβ amyloid-β, TLR4 toll-like receptor 4, MyD88 myeloid differentiation factor 88, TRAF-6 tumor necrosis factor (TNF) receptor-associated factor-6, TAK-1 transforming growth factor-β (TGF-β)-activated kinase-1, NF-κB nuclear factor-κB, JNK c-Jun N-terminal Kinase, NLRP3 nucleotide-binding oligomerization domain (NOD)-like receptor protein 3, IL-18 interleukin-18, IL-1β interleukin-1β, CD cluster of differentiation. Display omitted •Scoparone mitigated OVX/D-Gal-induced neuroinflammation and Alzheimer’s hallmarks.•Scoparone improved rats’ memory functions and the hippocampal photomicrographs.•Modulation of TLR4 axis by scoparone is a core signaling in mediating its effects.•NLRP3 inhibition and M2 microglial shifting underlie scoparone’s neuroprotection.•Scoparone is a prosperous candidate for Alzheimer’s disease management. Neuroinflammation mediated by microglia activation is a critical contributor to Alzheimer's disease (AD) pathogenesis. Dysregulated microglia polarization in terms of M1 overactivation with M2 inhibition is involved in AD pathological damage. Scoparone (SCO), a coumarin derivative, displays several beneficial pharmacological effects including anti-inflammatory and anti-apoptotic properties, however, its neurological effect in AD is still elusive. This study investigated the neuroprotective potential of SCO in AD animal model focusing on determining its effect on M1/M2 microglia polarization and exploring the plausible mechanism involved via investigating its modulatory role on TLR4/MyD88/NF-κB and NLRP3 inflammasome. Sixty female Wistar rats were randomly allocated into four groups. Two groups were sham-operated and treated or untreated with SCO, and the other two groups were subjected to bilateral ovariectomy (OVX) and received D-galactose (D-Gal; 150 mg/kg/day, i.p) alone or with SCO (12.5 mg/kg/day, i.p) for 6 weeks. SCO improved memory functions of OVX/D-Gal rats in the Morris water maze and novel object recognition tests. It also reduced the hippocampal burden of amyloid-β42 and p-Tau, additionally, the hippocampal histopathological architecture was prominently preserved. SCO inhibited the gene expression of TLR4, MyD88, TRAF-6, and TAK-1, additionally, p-JNK and NF-κBp65 levels were significantly curbed. This was associated with repression of NLRP3 inflammasome along with M1-to-M2 microglia polarization shifting as exemplified by mitigating pro-inflammatory M1 marker (CD86) and elevating M2 neuroprotective marker (CD163). Therefore, SCO could promote microglia transition towards M2 through switching off TLR4/MyD88/TRAF-6/TAK-1/NF-κB axis and inhibiting NLRP3 pathway, with consequent mitigation of neuroinflammation and neurodegeneration in OVX/D-Gal AD model.