Abstract: Objective: To explore the inhibitive effect and underlying mechanism of Morinda officinalis (MO) on human colorectal cancer cell HCT-116 xenograft tumor model. Methods: Xenograft tumor model was established through transplanting human colorectal cancer cell into the armpits of male nude mice. Four groups were divided for appropriate administration, including ethanol extract of Morinda officinalis (EEMO) group (12 mg/kg/d), crude drug of Morinda officinalis (CDMO) group(200 mg/kg/d), 5-fluorouracil (30 mg/kg, once per three days) group, control group (water, once a day). The administration of drugs was lasted for 23 days. Tumor weight, tumor volume and pathological changes were detected. Protein expression of Hypoxia inducible factor-1α (HIF-1α), Cyclooxygenase-2/Prostaglandin E2 (COX-2/PGE2) pathway and macrophage polarization were determined after the experiment. Results: Both EEMO and CDMO could significantly inhibited the weight and growth of HCT-116 xenograft tumor (P<0.01), lowered the content of PGE2 (P<0.05), reduced the expression of HIF-1α, COX-2 and VEGF in tumor (P<0.01 and P<0.05). Additionally, EEMO and CDMO could remarkably increase the ratio of M1-like macrophage phenotype in tumor microenvironment (P<0.01). Conclusion: MO exerted anti-tumor effect partly via inhibiting expression of HIF-1α, COX-2/PGE2 pathway and polarizing tumor-associated macrophages toward M1-like macrophage phenotype.