Probiotics have been used as one of the most promising dietary interventions to alleviate disease transmission in aquaculture. However, there are limited studies on probiotic uses in modulating the highly contagious virus such as tilapia lake virus (TiLV) that is seriously threatening global tilapia production. We assessed commercially available probiotic supplement use in TiLV-infected tilapia and performed mortality and cohabitation assays. We developed a mechanistic approach to predict dose-response interactions of probiotic effects on mortality and innate immune gene response. We used a susceptible-infected-mortality disease model to assess key epidemiological parameters known as transmission rate and basic reproduction number ( R 0) based on our viral load dynamics data. We found that the most marked benefits of probiotics are significantly associated with immune system enhancements (~30%) and disease transmission (~80%) and R 0 (~70%) reductions in tilapia populations, resulting in a higher tolerance of farming densities (~400 folds) in aquaculture. These findings provide early insights as to how probiotic use-related factors may influence TiLV transmission and the immune responses in TiLV-infected tilapia. Our study facilitates understanding the mode of action of probiotics in disease containment and predicting better probiotic dosages in diet and supplements to achieve the optimal culturing conditions. Overall, our analysis assures that further study of rationally designed and targeted probiotics, or mechanistic modeling is warranted on the basis of promising early data of this approach.