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Cancer stem cells (CSCs) drive tumour initiation, metastasis and therapeutic resistance through metabolic and microenvironmental adaptability. The microbiota critically modulates cancer development and treatment response, with increasing evidence linking commensal microbes and their metabolites to aberrant CSC function. In this review, we summarise the mechanistic roles of microbiota and metabolites (eg, short-chain fatty acids, bile acids) in CSC regulation, including their effects on the CSC niche via stromal cell modulation, extracellular matrix remodelling and soluble factor networks. Given the central roles of CSCs in chemoresistance, we further discuss how microbes and metabolites influence CSC-associated chemotherapy resistance and highlight microbiota-targeting and metabolite-targeting strategies including probiotics, metabolite formulations, antibiotics and nanomedicine to disrupt CSCs and enhance chemosensitivity. In summary, deeper insights into CSC–microbiota–metabolites crosstalk promise novel therapeutic targets to overcome resistance and improve patient outcomes.