Methamphetamine (Meth) can evoke extreme hyperthermia, which correlates with both neurotoxicity and death in laboratory animals and humans. The objective of this study was to uncover the mechanisms of a complex dose-dependence of temperature responses to Meth by mathematical modeling the neural circuitry involved. Based on previous studies, we composed an artificial neural network with the core comprised of three sequentially connected nodes: Excitatory, Medullary and sympathetic preganglionic SPN. Meth directly stimulated the Excitatory node, an inhibitory drive targeting the Medullary node, and in high doses - additional excitatory drive affecting the SPN. All model parameters (weights of connections, sensitivities, time constants) were subject to fitting experimental time series of temperature responses to 1, 3, 5, and 10 mg/kg of Meth. Modeling suggested that the temperature response to the lowest dose of Meth which caused an immediate and short hyperthermia, involves neuronal excitation at a supramedullary level. The delay in response seen after intermediate doses of Meth is a result of neuronal inhibition at the medullary level. Finally, the rapid and robust increase in body temperature induced by the highest dose of Meth involves activation of high-dose excitatory drive. The impairment in the inhibitory mechanism can provoke life-threatening temperature rise, and makes it a plausible cause of fatal hyperthermia in Meth users. We expect that studying putative neuronal sites of Meth action and involved neuromediators resulting in a detailed model of this system may lead to more effective strategies of prevention and treatment of hyperthermia induced by amphetamine­-like stimulants.