Cryptococcus spp., the causative agents of cryptococcosis, are responsible for deaths of hundreds of thousands of people every year worldwide. The drawbacks of available therapeutic options are aggravated by the increased resistance of yeast to the drugs, resulting in inefficient therapy. Also, the antifungal 5FC is not available in many countries. Therefore, a combination of antifungal drugs may be an interesting option, but in vitro and theoretical data point to the possible antagonism between the main antifungals used to treat cryptococcosis, i.e., fluconazole (FLC), and amphotericin B (AMB). Therefore, in vivo studies are necessary to test the above hypothesis. In this study, the efficacy of FLC and AMB at controlling C. gattii infection was evaluated in a murine model of cryptococcosis caused by C. gattii. The infected mice were treated with FLC + AMB combinations and showed a significant improvement in survival as well as reduced morbidity, reduced lung fungal burden, and the absence of yeast in the brain when FLC was used at higher doses, according to the Tukey test and principal component analysis. Altogether, these results indicate that combinatorial optimization of antifungal therapy can be an option for effective control of cryptococcosis.