Obesity, characterized by excessive fat accumulation, poses global health risks, including metabolic disorders like type 2 diabetes and cardiovascular diseases, with its prevalence steadily rising. This study proposes that rottlerin induces anti-obesity effects by enhancing non-shivering thermogenesis in beige adipocytes D16 via LRP6 inhibition. As a result, treatment of D16 cells with rottlerin up to 5 mM showed no cytotoxicity. Rottlerin significantly increased the expression of proteins involved in substrate oxidation, such as UCP1 and PGC1a, while decreasing the expression of C/EBPb associated with adipogenesis. Additionally, PRDM16, regulating brown adipocyte development, exhibited increased expression. The phosphorylation of LRP6, an indicator for Wnt signaling and nutrient-sensing pathway, is decreased by rottlerin. In conclusion, the study highlights the reduced phosphorylation of LRP6 as a pivotal mechanism by which rottlerin promotes the “beigeing” of D16 adipocytes, subsequently inducing non-shivering thermogenesis. This underscores rottlerin’s potential as a natural bioactive compound with anti-obesity effects.