Amphetamine (AMPH) exerts metabolic and cardiovascular effects. The central melanocortin system is a key regulator of both metabolic and cardiovascular functions. Here, we show that the melanocortin system partially mediates AMPH-induced anorexia, energy expenditure, tachycardia, and hypertension. AMPH increased α-melanocyte stimulating hormone (αMSH) secretion from the hypothalamus, elevated blood pressure and heart rate (HR), increased brown adipose tissue (BAT) thermogenesis, and reduced both food intake (FI) and body weight (BW). In melanocortin 4 receptor-deficient (MC4R knockout [KO]) mice, metabolic and cardiovascular effects of AMPH were significantly attenuated. Antagonism of serotonergic and noradrenergic neurotransmitter systems attenuated AMPH-induced αMSH secretion as well as AMPH-induced metabolic and cardiovascular effects. We propose that AMPH increases serotonergic activation of proopiomelanocortin (POMC) neurons and reduces the noradrenergic inhibition of POMC neurons, thereby disinhibiting them. Together, these presynaptic mechanisms result in increased POMC activity, increased αMSH secretion, and increased activation of MC4R pathways that regulate both the metabolic and cardiovascular systems.