Human coxsackievirus B3 (CVB3) and rotaviruses (RV), RNA viruses, are major heart and intestine pathogens in children, respectively. In the current study, we determined the effect of methanol extract from the leaves of Dodonaea viscosa against CVB3 and RV replication in vivo. BALB/c mice were injected intraperitoneally with CVB3 at 10 5 TCID 50 (50% tissue culture infective dose) or inoculated orally with RV at 10 6 TCID 50 , inducing acute myocarditis and gastroenteritis in infected mice. After 24 h of infection, the infected mice with CVB3 or RV were treated orally with the methanol extract of Dodonaea viscoasa leaves for 7 days. We found that the extract protected the infected mice from deaths and reduced the viral titers in heart tissues and fecal specimens of mice infected with CVB3 and RV, respectively. Interestingly, the extract showed markedly improved cardiac tissues and small intestinal lesion scores of infected mice with CVB3 and RV, respectively. Moreover, the extract reduced the elevation of the lactic dehydrogenase, Creatine kinase, and aspartate transaminase enzymes in serum of CVB3 infected mice. Also, the extract reduced the duration of diarrhea in the infected mice with RV, when compared with those in infected control. In our conclusion, the methanol extract could be used as strong therapeutic target for viral myocarditis and gastroenteritis caused by CVB3 and RV, respectively.