In vivo evaluation of antiviral compounds can serve as criteria in the drug discovery process for selection of compounds that are suitable to enter late preclinical studies and further development. Dengue virus serotypes 1-4 can infect and replicate in the interferon type I and type II receptor deficient mice (AG129). Here we describe the use of a mouse-adapted dengue 2 virus strain (S221) that has been used to develop a robust lethal model of infection. Treatment with small molecule inhibitors of DENV replication at the time of infection or delayed treatment up to 48 h post infection can result in measurable protection that reflects the efficacy of the tested compound.