Emilia sonchifolia L. (Asteraceae) is used in ethnomedicine for the treatment of a wide array of inflammatory disorders. This practice has also been supported by scientific reports which showed that extracts of E. sonchifolia possess anti-inflammatory effects in rodents. However, the mechanism(s) through which the extracts produce these effects is not known. In this study, the effect of a methanol/methylene chloride extract of E. sonchifolia (ES) on the levels of IL-1β and TNF-α after an intraperitoneal lipopolysaccharide (LPS; 1 mg/kg) challenge was investigated in mice. The effect of ES on TNF-α and inducible nitric oxide (iNO) production by LPS-stimulated bone marrow-derived macrophages (BMMDM) was also investigated in vitro. BMMDM were pre-incubated for 2 h with ES (20, and 100 μg/mL) or with Pyrrolidine dithiocarbamate, PDTC (100 µM) and then activated with LPS, and then the IL-1β, TNF-α and NO production measured in the cell-free conditioned culture supernatant after 24 h of incubation. In groups of mice pre-treated with ES, the systemic levels of IL-1β and TNF-α induced by LPS were found to be significantly (p < 0.05) lower. In vitro, ES treatment caused a concentration-dependent decrease in LPS-inducible IL-1β, TNF-α, and NO production by BMDM compared to the effects of treatment of the cells with LPS alone without affecting the viability of the cells. The results of these studies suggest that treatment with ES alleviated inflammatory responses possibly through a suppression of pro-inflammatory mediators and cytokines such as IL-1β, TNF-α, and iNO.