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Influenza A virus (IAV) H1N1 infection is a constant threat to human health and it remains so due to the lack of an effective treatment. Since melatonin is a potent antioxidant and anti-inflammatory molecule with anti-viral action, in the present study we used melatonin to protect against H1N1 infection under in vitro and in vivo conditions. The death rate of the H1N1-infected mice was negatively associated with the nose and lung tissue local melatonin levels but not with serum melatonin concentrations. The H1N1-infected AANAT-/- melatonin-deficient mice had a significantly higher death rate than that of the WT mice and melatonin administration significantly reduced the death rate. All evidence confirmed the protective effects of melatonin against H1N1 infection. Further study identified that the mast cells were the primary targets of melatonin action, i.e., melatonin suppresses the mast cell activation caused by H1N1 infection. The molecular mechanisms involved melatonin down-regulation of gene expression for the HIF-1 pathway and inhibition of proinflammatory cytokine release from mast cells; this resulted in a reduction in the migration and activation of the macrophages and neutrophils in the lung tissue. This pathway was mediated by melatonin receptor 2 (MT2) since the MT2 specific antagonist 4P-PDOT significantly blocked the effects of melatonin on mast cell activation. Via targeting mast cells, melatonin suppressed apoptosis of alveolar epithelial cells and the lung injury caused by H1N1 infection. The findings provide a novel mechanism to protect against the H1N1-induced pulmonary injury, which may better facilitate the progress of new strategies to fight H1N1 infection or other IAV viral infections. Author summary: IAV is one of the most common respiratory pathogens, leading to acute lung injury and a high morbidity rate. Melatonin has important regulatory roles in modulating immune responses during acute inflammatory conditions. It is of great significance to explore the protection effect of melatonin against the H1N1-induced pulmonary injury. Here, we found that melatonin had essential impacts on protection against IAV infection in mice. For the first time, we proved that melatonin had the capacity to suppress the activation of mast cells and the associated inflammatory response during H1N1 infection. The molecular mechanisms involved melatonin down-regulation of gene expression for the HIF-1 pathway mediated by MT2 and inhibition of proinflammatory cytokine release from mast cells, ultimately, leading to a reduction in the migration and activation of the macrophages and neutrophils in the lung tissue. Consequently, melatonin suppressed apoptosis of alveolar epithelial cells and the lung injury caused by H1N1 infection. Our findings highlight a novel mechanism to protect against the H1N1-induced pulmonary injury, and also provide insights into the new strategies to fight IAV infections. [ABSTRACT FROM AUTHOR]