<p>Neuroinflammation and oxidative stress (OS) are the major contributors to the onset and progression of neurodegenerative diseases (NDs), where microglial activation and dysregulated inflammatory signaling exacerbate neuronal injury. Nobiletin (NOB), a polymethoxylated flavonoid abundant in citrus fruits, has been reported to possess excellent bioactivities; however, its effects in combating inflammation and OS in human microglial cells (HMC3) have not been comprehensively examined. In this study, we investigated the effects of NOB on lipopolysaccharide (LPS)-induced inflammatory and oxidative responses in HMC3 cells. The HMC3 cells exposed to LPS (1&#xa0;µg/mL) in the presence/absence of NOB (5, 10, 20, and 40&#xa0;µM) for 24&#xa0;h showed that NOB could attenuate LPS-induced cytotoxicity. NOB treatment attenuated LPS-induced upregulation of pro-inflammatory cytokines including interleukin (IL)-1β, and IL-6, and suppressed activation of the toll-like receptor 4/myeloid differentiation primary response 88/nuclear factor kappa-light-chain-enhancer of activated B (TLR4/MyD88/NF-κB) pathway. NOB enhanced the protein expression levels of TLR10, a negative regulator of TLR4-mediated inflammatory signaling. In addition, NOB increased the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression, along with other antioxidants including catalase (CAT), glutathione peroxidase (GPx), and superoxide dismutase (SOD), leading to reduced intracellular reactive oxygen species (ROS). These findings suggest that NOB has promising anti-inflammatory and antioxidant effects in an in vitro model of LPS-induced neuroinflammation, potentially through modulation of TLR4/MyD88/NF-κB and Nrf2/HO-1 signaling pathways. However, further in vivo studies are needed to validate these effects and explore NOB’s potential as a candidate for therapeutic development in NDs.</p> Graphical Abstract <p></p>