The eating disorder anorexia nervosa is potentially fatal but also poorly understood. Sweeney et al. now show that AgRP (Agouti-related protein)–expressing neurons, previously linked to anorexic feeding behavior, regulate food intake via the melanocortin-3 receptor (MC3R). Chemogenetic and pharmacological approaches to control the MC3R in AgRP neurons bidrectionally altered feeding and anxiety-like behavior in male and female mice, with an MC3R antagonist and agonist promoting weight loss and gain, respectively. This study provides proof of principle for pharmacologically targeting MC3R in AgRP neurons to alter food intake.