Background and Objectives:We aimed to investigate the role ofWnt2expression in colorectal cancer (CRC) prognosis and evaluate its potential as a therapeutic target inBRAF-mutated CRC.Materials and Methods: Exactly 136 samples of formalin-fixed paraffin-embedded CRC tissue specimens were obtained from patients who underwent surgical resection for CRC. The gene mutation status of the samples was detected using fluorescence PCR.Wnt2expression was detected using immunohistochemistry. Survival curves with highWnt2expression andBRAFmutations were compared using the Kaplan–Meier method. A nomogram was constructed to determine the estimated overall survival probability. We also predicted the 3-year and 5-year survival rates for patients with highWnt2expression andBRAFmutations. In total, 50 samples ofBRAF-mutated CRC were collected and detectedWnt2expression by immunohistochemistry. The Chi-squared test was used to analyze the association betweenWnt2expression andBRAF-mutated CRC.Results: HighWnt2expression andBRAFmutations are associated with poor prognosis of CRC. Multivariate survival analyses indicated that highWnt2expression andBRAFmutations are significant independent predictors of CRC prognosis. Furthermore, highWnt2expression was significantly associated withBRAF-mutated CRC, andWnt2may be a potential therapeutic target forBRAF-mutated CRC.Conclusions: HighWnt2expression confers poor prognosis in colorectal cancer and represents a novel therapeutic target inBRAF-mutated CRC.