Natural resistance associated macrophage protein 1 (Nramp1) was discovered as a genetic determinant of resistance against multiple intracellular pathogens, including Leishmania. It encodes a transmembrane protein of the phago-endosomal vesicles, where it functions as an iron transporter. But how Nramp1 expression is regulated in an infected macrophage is unknown. Its role in controlling iron availability to the intracellular pathogens and in determining the final outcome of an infection also remains to be fully deciphered. Here we report that Nramp1 protein abundance undergoes temporal changes in Leishmania major infected macrophages. At 12 hours post infection, there was drastic lowering of Nramp1 level accompanied by increased phagolysosomal iron availability and enhanced parasite growth. Leishmania infection-induced downregulation of Nramp1 was found to be caused by ubiquitin-proteasome degradation pathway. In fact, blocking of Nramp1 degradation with proteasome inhibitor resulted in depletion of phagolysosomal iron pool with significant reduction in the number of intracellular parasites. Further, we uncovered that this degradation process is mediated by the iron regulatory peptide hormone hepcidin that binds to Nramp1. Interestingly, Nramp1 protein level was restored to normalcy after 30 hours of infection with a concomitant drop in the phagolysosomal iron level, which is suggestive of a host counter defense strategy to deprive the pathogen of this essential micronutrient. Taken together, our study implicates Nramp1 as a central player in the host-pathogen battle for iron. It also unravels Nramp1 as a novel partner for hepcidin. The hitherto unidentified 'hepcidin-Nramp1 axis' may have a broader role in regulating macrophage iron homeostasis.