The interleukin-6 (IL-6)/signal transducer and activator of transcription (STAT)-3 signaling pathway regulates survival and proliferation of intestinal epithelial cells, and has profound impact on the tumorigenesis of colitis-associated cancer (CAC). Tea polysaccharides (TPS) is the major nutraceutical component isolated from tea-leaves and is known to possess antioxidant, anti-inflammatory and antitumor bi-oactivities. Here, we investigated the antitumor activities of TPS on CAC using the azoxymethane/dextran sulfate sodium (AOM/DSS) mouse model and IL-6-induced colorectal cancer cell line (CT26), and determined whether TPS exerted its antitumor effects through the IL-6/STAT3 pathway. Results demonstrated that TPS significantly decreased the tumor incidence, tumor size, and markedly inhibited the infiltration of inflammatory cells and the secretion of inflammatory cytokines via balancing cellu-lar microenvironment. Furthermore, we found that TPS suppressed the activation of STAT3 and transcriptionally regulate the expressions of downstream genes including MMP2, cyclin Dl, survivin and VEGF, both in vivo and in vitro. Thus, it is concluded that TPS attenuate the progress of CAC via suppressing IL-6/STAT3 pathway and downstream genes’ expressions, which indicated that TPS may be a hopeful anti-tumor agent for the prevention and treatment of colon cancer.