Viral infections are a leading cause of morbidity and mortality worldwide. Clinical studies suggest that a diet rich in marine fatty acids present in fish-derived oil (FDO) may improve antiviral immunity. However, there is limited evidence for FDO antiviral properties, and which components should be considered when designing such a medical food. In this study designed as a clinical trial on healthy volunteers, we demonstrated a direct effect of FDOs on enhancing NK cell cytotoxicity and increase in IFN-γ synthesis, the main components of antiviral immunity. This effect was related to the presence of free fatty acid receptors type 1 and 4 on the lymphocyte surface, further upregulated during immune activation. These data allowed us to formulate an overall algorithm for designing medical foods based on FDO, including the percentage of main ingredients, in vitro efficacy evaluation, clinical daily dosage, and laboratory parameters useful for monitoring an immune response.