This study aimed to investigate the anti-inflammatory efficacy and mechanisms of heat-treated Liriope platyphylla (LP) ethanol extract. This was done by measuring nitric oxide (NO) levels, the gene expression of inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α, as well as chemokines like monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α), and inflammation-related proteins like cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS). Additionally, protein expression of COX-2 and iNOS was assessed, along with the modulation of the mitogen-activated protein kinase (MAPK) pathway involved in the inflammatory response, in lipopolysaccharide (LPS)-treated macrophages. Treatment with the heat-treated LP ethanol extract at concentrations of 12.5, 25, 50, and 100 μg/mL, which were not cytotoxic, resulted in a significant reduction in NO production. particularly at the 100 μg/mL concentration. The gene expression levels of inflammatory cytokines, chemokines, and inflammation-related proteins were measured using qRT-PCR. Notably, the gene expression levels of IL-1β, TNF-α, MCP-1, MIP-1α, and COX-2 showed a dose-dependent decrease upon treatment with the extract, while IL-6 and iNOS were significantly inhibited at a concentration of 100 μg/mL. Furthermore, the study found a reduction in the protein expression of COX-2 and iNOS, as well as in the MAPK signaling pathway, when cells were treated with the heat-treated LP ethanol extract. These results indicate that the heat-treated LP ethanol extract exerts an anti-inflammatory effect, mediated through the inhibition of inflammatory cytokines, chemokines levels, and MAPK activation.