Double-stranded RNA (dsRNA) is well characterized as an inducer of antiviral interferon responses. We previously reported that dsRNA extracted from a specific edible plant possesses immune-modulating capacity to confer mice the resistance against respiratory viruses, including the H1N1 strain of the Influenza A virus. We report that the systemic immune-activating capacity of the plant-derived dsRNA protected mice from infection by a highly virulent H5N1 strain of the Influenza A virus. In addition, subcutaneous inoculation of the dsRNA together with inactivated virion of the H5N1 strain of the Influenza A virus suppressed the lethality by the viral infection as compared with individual inoculation of either dsRNA or HA protein, suggesting its potential usage as a vaccination adjuvant. Moreover, intraperitoneal inoculation of the dsRNA limited the growth of B16-F10 melanoma cells through the activation of NK cells in murine models. Taken together, this study demonstrated the systemic immune-modulating capacity of a plant-derived dsRNA and its potential for nucleic acid-based clinical applications.