OBJECTIVES: The gut microbiome (GM) is pivotal in regulating inflammation, immune responses, and cancer progression. This study investigates the effects of a ketogenic diet (KD) and a high-fat/low-carbohydrate (HF/LC) diet on GM alterations and tumor growth in a syngeneic mouse model of high-grade serous ovarian cancer (EOC). METHODS: Thirty female C57BL/6J mice injected with KPCA cells were randomized into KD, HF/LC, and low-fat/high-carbohydrate (LF/HC) diet groups. Tumor growth was monitored with live, in vivo imaging. Stool samples were collected at the time of euthanasia and analyzed by 16SrRNA sequencing and shotgun metagenomic sequencing was performed to identify differential microbial taxonomic composition and metabolic function. RESULTS: Our findings revealed that KD and HF/LC diets significantly accelerated EOC tumor growth compared to the LF/HC diet in a xenograft model. GM diversity was markedly reduced in KD and HF/LC-fed mice, correlating with increased tumor growth, whereas LF/HC-fed mice showed higher GM diversity. Metagenomic analyses identified distinct alterations in microbial taxa including , , Bacterium_D16_50, and predominantly abundant in HF/LC-fed mice, predominantly abundant in LF/HC-fed, and KD fed mice showing a higher abundance of and . Functional pathways across diet groups indicated polyamine biosynthesis and fatty acid oxidation pathways were enriched in HF/LC-fed mice. CONCLUSIONS: These results highlight the intricate relationship between diet, the gut microbiome, and tumor metabolism. The potential role of dietary interventions in cancer prevention and treatment warrants further investigation.