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Ursolic acid (UA) is a triterpenoid phytochemical with a strong anticancer effect. The metabolic rewiring, epigenetic reprogramming, and chemopreventive effect of UA in prostate cancer (PCa) remain unknown. Herein, we investigated the efficacy of UA in PCa xenograft, and its biological effects on cellular metabolism, DNA methylation, and transcriptomic using multi‐omics approaches. The metabolomics was quantified by liquid‐chromatography–mass spectrometry (LC‐MS) while epigenomic CpG methylation in parallel with transcriptomic gene expression was studied by next‐generation sequencing technologies. UA administration attenuated the growth of transplanted human VCaP‐Luc cells in immunodeficient mice. UA regulated several cellular metabolites and metabolism‐related signaling pathways including S‐adenosylmethionine (SAM), methionine, glucose 6‐phosphate, CDP‐choline …