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Cow mastitis is a major problem frequently encountered by dairy farmers and it is manifested by the high number of somatic cells and the low quality of the milk. The conventional treatment for mastitis is use of antibiotics. In the current study, a new approach is applied to target this disorder: rumen bypass melatonin feeding (RBMF). The RBMF significantly reduced milk somatic cell count and improved milk nutritional values with the elevated protein, fat and dry matter levels. This approach also suppresses the stress and proinflammatory responses of the cows indicated by the reduced serum cortisol, TNF-α and IL-6 and increased IL-10 levels. Importantly, the beneficial effects of RBMF have lasted for several days after termination of the treatment. The effects of melatonin on the mastitis are probably attributed to the antioxidant and anti-inflammatory activities of melatonin. Considering the none or low toxicity of melatonin to organisms and the no invasive nature of this approach, we recommend that RBMF could be used in large scale in the dairy farming to target the cow mastitis.