With the ability of viruses to mutate and introduce a high rate of diversity and continuous resistance to drug development, unique solutions are needed. RNA interference (RNAi) pathway as a natural defense mechanism mediated by plants, invertebrates, and vertebrates displayed a promising gene silencing platform through high sequence-specific technique. Non–coding small interfering RNA (siRNA) as a member of RNAi successfully inhibited many different viruses efficiently and can be designed against any viruses even very small ones. This highly conserved silencing mechanism involved many steps and components to knock down any gene and there are many criteria that influence siRNA efficiency and specificity. RNAi technology attracts the scientific community since its discovery with continuous developments regarding siRNA design, bioinformatics tools, and their delivery to cells. In this mini-review, we discussed the basic pathway of siRNA, their antiviral role, efficient delivery to cells, and the critical factors that affect their efficiency and specificity.