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Invasive fungal infections are a significant public health concern, with mortality rates ranging from 20% to 85% despite current treatments. Therefore, we examined whether a ketogenic diet could serve as a successful treatment intervention in murine models of Cryptococcus neoformans and Candida albicans infection in combination with fluconazole-a low-cost, readily available antifungal therapy. The ketogenic diet is a high-fat, low-carbohydrate diet that promotes fatty acid oxidation as an alternative to glycolysis through the production of ketone bodies. In this series of experiments, mice fed a ketogenic diet prior to infection with C. neoformans and treated with fluconazole had a significant decrease in fungal burden in both the brain (mean 2.66 ± 0.289 log 10 reduction) and lung (mean 1.72 ± 0.399 log 10 reduction) compared to fluconazole treatment on a conventional diet. During C. albicans infection, kidney fungal burden of mice in the keto-fluconazole combination group was significantly decreased compared to fluconazole alone (2.37 ± 0.770 log 10 -reduction). Along with higher concentrations of fluconazole in the plasma and brain tissue, fluconazole efficacy was maximized at a significantly lower concentration on a keto diet compared to a conventional diet, indicating a dramatic effect on fluconazole pharmacodynamics. Our findings indicate that a ketogenic diet potentiates the effect of fluconazole at multiple body sites during both C. neoformans and C. albicans infection and could have practical and promising treatment implications.IMPORTANCEInvasive fungal infections cause over 2.5 million deaths per year around the world. Treatments for fungal infections are limited, and there is a significant need to develop strategies to enhance antifungal efficacy, combat antifungal resistance, and mitigate treatment side effects. We determined that a high-fat, low-carbohydrate ketogenic diet significantly potentiated the therapeutic effect of fluconazole, which resulted in a substantial decrease in tissue fungal burden of both C. neoformans and C. albicans in experimental animal models. We believe this work is the first of its kind to demonstrate that diet can dramatically influence the treatment of fungal infections. These results highlight a novel strategy of antifungal drug enhancement and emphasize the need for future investigation into dietary effects on antifungal drug activity., Competing Interests: J.R.P. received grants/consulting support from Appili, Pfizer, Matinas, Cidara, Scynexis, and F2G. C.D.G. received past salary support from projects funded by Appili, Astellas, Amplyx, Interventional Analgesix, Minnetronix, Pfizer, and Sfunga Therapeutics. He owns common stock totaling less than $5,000 of the following: GSK, Actinium, Nkarta, and Bristol Myers Squibb. W.H. holds or has recently held research grants with UKRI, EU (FP7, IMI-1, and IMI-2), Wellcome, F2G, Spero Therapeutics, Antabio, Pfizer, Allecra, Bugworks, Phico Therapeutics, BioVersys, and Global Antimicrobial Research and Development Partnership (GARDP). He is (or has recently been) a consultant for Appili Therapeutics, F2G, Spero Therapeutics, Pfizer, GSK, Phico Therapeutics, Pulmocide, and Mundipharma Research Ltd. He was a member of the Specialist Advisory Committee for GARDP (2020–2023), a member of the British Society for Antimicrobial Chemotherapy Breakpoint Committee (2020–2023), and a member of NIHR Health Technology Appraisal (HTA) Prioritisation Committee for hospital care and is the Specialty National Co-lead for Infection for the National Institute of Health Research (NIHR) (2020–current).