Cancer threatens the health and lives of people around the world and causes a heavy economic burden on families and society. Dysbiosis of the gut microbiota has been observed in cancer patients and is an important factor in cancer progression. Quercetin, a widely distributed dietary flavonol, exhibits pleiotropic anti-cancer activities in preclinical models. Importantly, recent studies reveal a bidirectional crosstalk between quercetin and the gut microbiota that may critically shape its biological effects. Specifically, gut microbiota enzymes mediate quercetin biotransformation and produce tumor-suppressive quercetin metabolites. On the other hand, quercetin remodels specific gut microbial species and their metabolites to promote anti-tumor activity. This review provides a timely and systematic synthesis of the latest findings regarding quercetin, gut microbiota, and cancer. Furthermore, we discuss strategies to enhance this interaction for improved cancer therapy. By highlighting the pivotal role of the gut microbiota, this review offers novel insights and a refined theoretical framework to guide future research and potential clinical translation of quercetin in cancer prevention and treatment.