Alpha (α)-tomatine is the major saponin and occurs naturally in tomatoes, which has been confirmed to possess a variety of biological properties including antitumoral, antioxidant, and anti-inflammatory. However, the anti-inflammatory mechanism of α-tomatine is not well understood. This study aims to investigate the anti-inflammatory effects and mechanisms of α-tomatine. Results showed that α-tomatine significantly suppressed the production of pro-inflammatory cytokines in lipopolysaccharide (LPS)-induced macrophages. Moreover, LPS-mediated nuclear translocation of the nuclear factor-kappaB (NF-κB)-p65 and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 were attenuated after α-tomatine treatment. Still, LPS slightly promoted phosphorylation of Akt, and α-tomatine accelerated the phosphorylation of Akt in macrophages. Our findings indicate that α-tomatine may be a valuable therapeutic agent in the treatment of inflammation-related diseases.