Cryptococcus spp., important fungal pathogens, are the leading cause of fungus-related mortality in human immunodeficiency virus-infected patients, and new therapeutic options are desperately needed. Isavuconazonium sulfate, a newer triazole antifungal agent, was studied to characterize the exposure-response relationship in a rabbit model of cryptococcal meningoencephalitis. Rabbits treated with isavuconazonium sulfate were compared with those treated with fluconazole and untreated controls. The fungal burden in the cerebrospinal fluid was measured serially over time, while the yeast concentrations in the brain and the eye (aqueous humor) were determined at the end of therapy. The exposure impact of isavuconazonium sulfate dosing in the rabbit was linked using mathematical modeling. Similar significant reductions in the fungal burden in the brain and cerebrospinal fluid in rabbits treated with isavuconazonium sulfate and fluconazole compared with that in the untreated controls were observed. No dose-dependent response was demonstrated with isavuconazonium sulfate treatment in this study. The treatment of cryptococcal meningoencephalitis with isavuconazonium sulfate was similar to that with fluconazole. Dose-dependent reductions in yeast over time were not demonstrated, which limited our ability to estimate the pharmacodynamic target. Further nonclinical and clinical studies are needed in order to characterize the extent of the exposure-response relationship in cryptococcal meningoencephalitis. However, this study suggests that isavuconazonium sulfate, like fluconazole, could be beneficial in the setting of consolidation and maintenance therapy, rather than induction monotherapy, in high-burden cryptococcal meningoencephalitis.