Diet-induced obesity in mice and humans is commonly associated with an imbalance between energy intake and expenditure. Reportedly, creatine can enhance energy expenditure in brown adipose tissue and reduce hepatic triglycerides accumulation; however, the molecular mechanism underlying the role of exogenous creatine supplementation in regulating lipid droplet mobilization remains elusive. Herein, we employed a high-fat diet (HFD)- induced mouse model to investigate the role of creatine in regulating lipolysis and lipophagy in brown adipose tissue and the liver. Exogenous creatine supplementation ameliorated HFD-induced obesity, increased insulin sensitivity and improved glucose homeostasis. Creatine supplementation enhanced the expression of uncoupling protein 1 (UCP1), cell death-inducing DNA fragmentation factor alpha-like effector A (CIDEA), and other brown adipose tissue-specific thermogenic genes Cpt1a, Gyk, and Pgc1β in brown adipose tissue. Furthermore, creatine inhibited the expression of CIDEA, which promotes hepatic lipid accumulation. Creatine stimulated the expression of triglyceride lipase adipose triglyceride lipase, and phospho-hormone-sensitive lipase (HSL) induced increased lipolysis in brown adipose tissue and the liver. Meanwhile, reduced LC3B expression was accompanied by an increased level of p62 in HFD-fed mice, indicating diminished basal autophagy in brown adipose tissue and the liver; however, creatine enhanced P62/LC3B induced lipophagy in brown adipose tissue and the liver. Collectively, our results suggest that creatine may function as a brown adipose tissue activator to increase whole-body energy metabolism via coordinated lipolysis and lipophagy in brown adipose tissue and the liver.