BACKGROUND: Neuroinflammation is a key pathological feature in many neurodegenerative diseases, and the nuclear factor kappa-B (NF-κB) signaling pathway is a central mediator of this response. Aged garlic extract (AGE) is a functional food with well-documented antioxidant and anti-inflammatory properties, but its role in mitigating neuroinflammation remains unclear. OBJECTIVE: This study investigates the effects of AGE on neuroinflammation by modulating the NF-κB signaling pathway using multi-omics analyses and experimental validation. DESIGN: Lipopolysaccharide (LPS)-induced BV2 microglial cells and LPS-treated C57BL/6 mice were used to assess the effects of AGE. Transcriptomics, metabolomics, and network pharmacology approaches identified potential targets and pathways, focusing on NF-κB signaling. In vitro and in vivo models were employed to evaluate behavioral, biochemical, and histological outcomes. RESULTS: AGE reduced pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-1β, inducible nitric oxide synthase, and cyclooxygenase-2) in LPS-stimulated BV2 cells and suppressed microglial activation and neuronal damage in LPS-induced mice. Transcriptomic analysis showed that NF-κB pathway inhibition mediated these effects, with molecular docking confirming interactions between aged garlic compounds and NF-κB targets (NF-κB2 and NF-κB3). CONCLUSION: AGE attenuates neuroinflammation by inhibiting the NF-κB signaling pathway, improving cognitive and motor functions, and reducing neuronal injury in experimental models. These findings suggest aged garlic as a promising neuroprotective agent against neuroinflammation.