Silibinin, the major active component of silymarin, is a flavonoid extracted from milk thistle and consists of a mixture of silibinin A and silibinin B. It has been previously reported to possess antioxidant and anti-inflammatory properties and has been investigated for its therapeutic potential in cancer treatment. Recently, increasing attention has been paid to its anti-obesity effects, as obesity is closely associated with inflammation and oxidative stress. This study is the first to investigate the relationship between silibinin and its anti-obesity effects in Caenorhabditis elegans. Our results showed that treatment with 100 μM silibinin significantly reduced triglyceride levels in worms compared to the control group. In addition, phenotype parameters, including pharyngeal pumping rate and body bending rate, were measured; a significant reduction in pharyngeal pumping was observed, while there was no significant reduction in the worms’ body bending rate. Consistently, a bacteria-clearing assay demonstrated that the amount of E.coli OP50 remaining in the treatment group was significantly higher than that in the control group. Both of the findings suggest silibinin could reduce the food intake in C. elegans. To elucidate the underlying mechanisms, mutant strains were employed. Silibinin did not exhibit a significant fat-reducing effect in eat-2 mutants, suggesting that its lipid-lowering activity is mediated through the suppression of food intake. Furthermore, no reduction in fat accumulation was observed in daf-12 null mutants after 48 hours of silibinin treatment. However, whether daf-12 is directly or indirectly affected by silibinin remains to be determined. Further studies are required to elucidate the signaling pathways regulated by daf-12.