Spilanthes acmella Murr. (S. acmella) has been used traditionally in India and Sri Lanka to treat various inflammatory diseases. However, the anti‑inflammatory effects and underlying mechanism of action of S. acmella are unclear. The present study assessed the anti‑inflammatory properties of methanol extracts of S. acmella (MSA) in murine macrophages. MSA (≤300 µg/ml) inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)‑stimulated RAW 264.7 macrophages through transcriptional inhibition of inducible nitric oxide synthase expression in a dose‑dependent manner. Furthermore, the LPS‑induced prostaglandin E2 production and cyclooxygenase‑2 expression were inhibited by MSA (300 µg/ml). MSA treatment inhibited interleukin (IL)‑6 production and decreased the mRNA expression levels of proinflammatory cytokines, including IL‑6 and IL‑1β. In addition, no significant inhibition in tumor necrosis factor‑α production was detected. Inhibitory effects of MSA on the production of inflammatory mediators were mediated by reduced activation of mitogen‑activated protein kinases (MAPKs) and nuclear factor (NF)‑κB. The LPS‑induced phosphorylation of transforming growth factor beta‑activated kinase 1, an upstream kinase of both MAPKs and NF‑κB, was also inhibited by MSA treatment. Taken together, MSA inhibits the excessive inflammatory responses in LPS‑stimulated murine macrophages by inhibiting the phosphorylation of MAPKs and NF‑κB, implicating S. acmella in the treatment of severe inflammatory states based on its ethnopharmacological importance and its anti‑inflammatory properties.