There are few animal models of dengue infection, especially in immunocompetent mice. Here, we describe alterations found in adult immunocompetent mice inoculated with an adapted Dengue virus (DENV-3) strain. Infection of mice with the adapted DENV-3 caused inoculum-dependent lethality that was preceded by several hematological and biochemical changes and increased virus dissemination, features consistent with severe disease manifestation in humans. IFN-γ expression increased after DENV-3 infection of WT mice and this was preceded by increase in expression of IL-12 and IL-18. In DENV-3-inoculated IFN-γ^−/− mice, there was enhanced lethality, which was preceded by severe disease manifestation and virus replication. Lack of IFN-γ production was associated with diminished NO-synthase 2 (NOS2) expression and higher susceptibility of NOS2^−/− mice to DENV-3 infection. Therefore, mechanisms of protection to DENV-3 infection rely on IFN-γ-NOS2-NO-dependent control of viral replication and of disease severity, a pathway showed to be relevant for resistance to DENV infection in other experimental and clinical settings. Thus, the model of DENV-3 infection in immunocompetent mice described here represents a significant advance in animal models of severe dengue disease and may provide an important tool to the elucidation of immunopathogenesis of disease and of protective mechanisms associated with infection. Dengue is a mosquito-borne disease caused by one of four serotypes of Dengue virus (DENV-1-4). Dengue has escalated in geographic distribution and disease severity to become the most common arboviral infection of humans. There are no vaccines or specific therapies for dengue and the treatment is supportive. Immunopathogenesis of dengue disease is also poorly understood, in part, due to of the absence of proper animal models of infection. Here, we describe the phenotype of infection of immunocompetent mice with an adapted DENV-3 strain. Infection caused an inoculum-dependent lethality that was preceded by significant clinical, virological and biochemical changes resembling the severe manifestations of human infection. In addition, we demonstrate that IFN-γ production is essential for the host to deal with DENV-3 infection in a manner similar to that demonstrated previously for DENV-2. Hence, reduced IFN-γ production during DENV-3 infection was associated with diminished NOS2 expression and Nitric oxide production. Mice deficient for each of these molecules presented more severe disease manifestation and increased viral replication. Therefore, we describe a model of DENV-3 infection in immunocompetent mice that proves to be an interesting tool to study host–virus interactions and mechanisms mediating protection or those associated with severe disease manifestation.