Zika virus (ZIKV) is a mosquito-borne flavivirus that has drawn worldwide attention due to its association to neurologic complications, particularly severe congenital malformations. While ZIKV can replicate efficiently and cause disease in human hosts, it fails to replicate to substantial titers in mice except when these lack IFN-I immunity (i.e. IFNAR1−/− or STAT1−/− mice). In this study, having in mind that immunocompromised mice are not ideal for studying the complex interplay of ZIKV infection with the host's immune defenses, we developed a murine model where lethal infection is induced in WT mice by introducing the virus directly in the brain via intracerebral (i.c.) inoculation. In this way, the antigen is precisely placed at the site of interest, evading the first line of defense, and thus rendering the mice susceptible to infection. We found that, while intravenous (i.v.) inoculation of two different strains of WT mice with low doses of ZIKV does not result in viremia, it is nevertheless able to induce both cell-mediated and humoral immunity as well as clinical protection against subsequent i.c challenge with lethal doses of the virus. In order to determine the contribution of key components of the immune system to the observed protection we employed several KO strains as well as in vivo T-cell depletion and adoptive transfer assays. So far, our results point to a key role for antiviral Abs in clinical protection; however, in the absence of preexisting Abs a minor impact of cell mediated immunity is revealed.