Neuropeptide Y (NPY) is a strong orexigenic neurotransmitter also known to modulate several neuroendocrine axes. α‐Melanocyte‐stimulating hormone (MSH) is an essential anorectic neuropeptide, acting on hypothalamic MC3/4 receptor subtypes. When given as an intracerebroventricular bolus injection, Melanotan‐II (MT‐II), a non selective MC receptor agonist, inhibits feeding, suppresses the NPY orexigenic action, and reduces basal insulinaemia. We evaluated the effects of a 7‐day central infusion of MT‐II (15 nmol/day) given either alone or in association with NPY (5 nmol/day) in male Sprague‐Dawley rats. MT‐II produced almost full anorexia for 1–2 days but then feeding gradually returned to normal despite continued MT‐II infusion. When coinfused with NPY, MT‐II also produced the same initial anorectic episode but then maintained feeding to upper normal levels, thus cancelling the hyperphagia driven by NPY. Whereas NPY infusion produced a doubling of fat pad weight, MT‐II reduced adiposity by a factor of two compared to pair‐fed rats, and vastly curtailed the NPY‐driven increase in fat pad weight. MT‐II infusion also significantly curtailed the NPY‐induced rise in insulin and leptin secretions. NPY infusion significantly inhibited hypothalamic pro‐opiomelanocortin mRNA expression, most likely cancelling the α‐MSH anorectic activity. As expected from previous studies, chronic NPY infusion strongly inhibited both the gonadotropic and somatotropic axes, and coinfusion of MT‐II did not reverse these NPY‐driven effects, in sharp contrast with that seen for the metabolic data. MT‐II infusion alone had little effect on these axes. In conclusion, chronic MT‐II infusion generated a severe but transient reduction in feeding, suggesting an escape phenomenon, and clearly reduced fat pad size. When coinfused with NPY, MT‐II was able to cancel most of the NPY effects on feeding, but not those on the neuroendocrine axes. It appears therefore that, as expected, NPY and α‐MSH closely interact in the control of feeding, whereas the neural pathways by which NPY affects growth and reproduction are distinct and not sensitive to MC peptide modulation.