Accumulating evidence indicates that adipose tissue inflammation and mitochondrial dysfunction in skeletal muscle are inextricably linked to obesity and insulin resistance. Celastrol, a bioactive compound derived from the root of Tripterygium wilfordii exhibits a number of attributive properties to attenuate metabolic dysfunction in various cellular and animal disease models. However, the underlying therapeutic mechanisms of celastrol in the obesogenic environment in vivo remain elusive. Therefore, the current study investigated the metabolic effects of celastrol on insulin sensitivity, inflammatory response in adipose tissue and mitochondrial functions in skeletal muscle of the high fat diet (HFD)-induced obese rats. Our study revealed that celastrol supplementation at 3 mg/kg/day for 8 weeks significantly reduced the final body weight and enhanced insulin sensitivity of the HFD-fed rats. Celastrol noticeably improved insulin-stimulated glucose uptake activity and increased expression of plasma membrane GLUT4 protein in skeletal muscle. Moreover, celastrol-treated HFD-fed rats showed attenuated inflammatory responses via decreased NF-κB activity and diminished mRNA expression responsible for classically activated macrophage (M1) polarization in adipose tissues. Significant improvement of muscle mitochondrial functions and enhanced antioxidant defense machinery via restoration of mitochondrial complexes I + III linked activity were effectively exhibited by celastrol treatment. Mechanistically, celastrol stimulated mitochondrial biogenesis attributed by upregulation of the adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) signaling pathways. Together, these results further demonstrate heretofore the conceivable therapeutic mechanisms of celastrol in vivo against HFD-induced obesity mediated through attenuation of inflammatory response in adipose tissue and enhanced mitochondrial functions in skeletal muscle.