Homeostatic control of energy balance is tightly regulated by a complex network of neurons involving orexigenic NPY/AgRP and anorexigenic POMC-expressing neurons situated within the arcuate nucleus of the hypothalamus. These neuronal populations receive and integrate information coming from afferent neurons, circulating nutrients, and hormones like insulin to maintain whole body energy balance. Dysregulation in this tightly regulated relay of energy status information between the brain and the periphery is the primary cause of the development of obesity. Here, we report that hypothalamic expression of Salt-Inducible Kinase 3 (SIK3), a serine/threonine protein kinase that regulates multiple signaling pathways involved in metabolic regulation, is increased in high-fat diet- and genetically-induced obese mice. Moreover, NPY neuron-specific deletion of SIK3 attenuated diet-induced obesity, enhanced energy expenditure via increased thermogenesis, and improved overall glucose homeostasis in mice. These effects are mainly driven by enhanced insulin signaling. In mice deficient in SIK3 in NPY neurons, insulin-induced AKT activation was significantly upregulated. Consistently, pharmacological inhibition of SIK3 in cells also resulted in increased AKT activation while overexpression of SIK3 resulted in a significant reduction in AKT phosphorylation in vitro. Our findings casually associate elevated SIK3 with the development of obesity. Additionally, our findings reveal a previously unidentified role of SIK3 inhibition in promoting negative energy balance via enhancing insulin signaling to attenuate diet-induced obesity.