Previous studies have shown that vaccination with heat-killed yeast, Saccharomyces cerevisiae (HKY), protects mice against systemic candidiasis, aspergillosis, cryptococcosis or coccidioidomycosis. Here we sought to define the potential use of HKY as a vaccine to protect mice from mucormycosis. Mice were vaccinated with different regimens of HKY prior to induction of diabetes. Diabetic ketoacidotic (DKA) mice were then treated with steroids prior to intratracheal challenge with Rhizopus oryzae. All regimens of HKY vaccine improved survival of DKA mice and reduced fungal burden in the primary target organ, lungs, as determined by qPCR. Furthermore, compared to mice vaccinated with diluent, vaccination with HKY substantially increased the mouse immune response as determined by detection of increased anti-Rhizopus antibody titers. Our results show that HKY protects steroid-treated DKA mice from pulmonary R. oryzae infection. Considering its demonstrated efficacy against other fungal infections, HKY is a promising candidate for development as a panfungal vaccine.