Many researchers have argued that Western diet (WD)-induced obesity accelerates inflammation and that inflammation is a link between obesity and colorectal cancer (CRC). This study investigated the effect of WDs on the development and progression of colitis-associated colon cancer (CAC) and the efficacy of the anti-obesity agent orlistat on WD-driven CAC in mice. The results revealed that the WD exacerbated CAC in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced mice, which showed increased mortality, tumor formation, and aggravation of tumor progression. Furthermore, WD feeding also upregulated inflammation, hyperplasia, and tumorigenicity levels through the activation of STAT3 and NF-κB signaling in an AOM/DSS-induced mouse model. In contrast, treatment with orlistat increased the survival rate and alleviated the symptoms of CAC, including a recovery in colon length and tumor production decreases in WD-driven AOM/DSS-induced mice. Additionally, orlistat inhibited the extent of inflammation, hyperplasia, and tumor progression via the inhibition of STAT3 and NF-κB activation. Treatment with orlistat also suppressed the β-catenin, slug, XIAP, Cdk4, cyclin D, and Bcl-2 protein levels in WD-driven AOM/DSS-induced mice. The results of this study indicate that orlistat alleviates colon cancer promotion in WD-driven CAC mice by suppressing inflammation, especially by inhibiting STAT3 and NF-κB activation.