The therapeutic effect of sustained intravitreal injectable voriconazole microspheres (VCZ-MS) on experimental endophthalmitis caused by Aspergillus fumigatus was investigated. VCZ-MS were prepared and evaluated. Vitrectomy was performed on rabbits after intravitreal inoculation of susceptible A. fumigatus. The animals were randomly divided into five groups, including control (no treatment after vitrectomy), vitrectomy plus voriconazole intravitreal injection, and vitrectomy plus intravitreal injection of VCZ-MS containing 0.5, 1.0, or 1.5 mg of voriconazole. The therapeutic effect was assessed at different time intervals. Voriconazole concentrations were monitored in the vitreous injected with VCZ-MS containing 1.0 mg of voriconazole. The results showed that endophthalmitis occurred in all eyes of the control group and rapidly developed into panophthalmitis. The inflammation in the voriconazole and VCZ-MS groups was mild, and in the groups treated with VCZ-MS containing 1.0 or 1.5 mg voriconazole, the inflammation was controlled, the vitreous was clear in all eyes, and there was no recurrence of endophthalmitis. Histopathological examination showed normal structures in the cured eyes, while most uncured eyes were atrophied. Therefore, it can be concluded that an intravitreal injection of VCZ-MS in addition to vitrectomy is an effective treatment for A. fumigatus-induced endophthalmitis in rabbits.