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Most cancer cells generate energy through aerobic glycolysis to enable their rapid growth and proliferation, which is a phenomenon known as Warburg effect. Inhibition of aerobic glycolysis reduces lactate and ATP generation in cancer cells, and ultimately kills tumor cells. Increasing evidence suggests that wogonin, a flavonoid isolated from Scutellaria baicalensis Georgi, exhibits potent anti-tumor effects in vivo and in vitro. However, the role of wogonin in the aerobic glycolysis of tumor cells has not yet been elucidated. In this study, the effect of wogonin on glucose uptake, lactate generation and ATP content is assessed in colon, ovarian and hepatocellular cancer cells. The results indicate that wogonin reduces glycolysis and cell proliferation in cancer cells expressing wild-type p53 but not mutated p53. Wogonin increases the expression of p53 and p53-inducible glycolysis and apoptosis regulator (TIGAR), while decreases glucose transporter 1 (GLUT1) and some key glycolytic enzymes. Expressing wild-type and mutant-type p53 in HCT116 p53−/− cells proved that the inhibitory effect of wogonin on glycolysis in cancer cells is dependent on wild type p53. Mechanistically, wogonin induced the phosphorylation and acetylation of p53 and inhibited the expression of MDM2 to enhance the stability of p53. Furthermore, wogonin suppressed the growth and glycolysis of transplanted wild-type p53 expressing A2780 cells on nude mice, but did not affect mutant-type p53 expressing HT-29 cells. In conclusion, these findings explain the broad anti-tumor effect of wogonin, and offer a novel avenue for the therapeutic strategy in cancer.