Biopesticides are promising alternatives to chemical pesticides because of their low residual effects, high selectivity, and capacity for long-term disease control. Melatonin (N-acetyl-5-methoxytryptamine) may be an ideal candidate for biopesticide because it is widely present in the plant kingdom, involved in growth, development, and stress-induced responses in plants, and can inhibit the growth and propagation of some microbial pathogens. However, it remains largely unclear whether melatonin influences rice and the blast fungus Magnaporthe oryzae. Here, we demonstrate that melatonin enhances rice immunity and inhibits the growth of M. oryzae, resulting in resistance to rice blast disease. Melatonin acts in rice response to M. oryzae because biosynthesis-related genes are induced upon M. oryzae infection. Melatonin treatment remarkably reduces blast disease severity in a susceptible rice accession. Mechanistically, melatonin treatment activates the mitogen-activated protein kinase cascades and up-regulates the expression of defense-related genes. Melatonin treatment also significantly inhibits the growth, sporulation, and spore germination of M. oryzae. Notably, melatonin treatment results in the death of M. oryzae hyphal cells. Altogether, our findings indicate that melatonin plays dual roles in the rice-M. oryzae interactions, activating rice immunity and inhibiting fungal growth. Thus, this study offers insights into the potential development of novel melatonin-based biopesticides for controlling rice blast disease.