Hypertension and diabetes mellitus are common comorbidities of colorectal cancer. We designed a prospective cohort study aiming to investigate the impact of long-term antihypertensive and antidiabetic medications on colorectal cancer-specific survival and recurrence among 713 post-surgical patients. All participants received radical resection for colorectal cancer during 2000-08, and they were followed up until July 2017. Colorectal cancer patients without hypertension had better survival than those with hypertension (median survival time [MST]: 190.3 months versus 99.0 months, p <0.001). The impact of antidiabetic medications on prolonging colorectal cancer survival was statistically significant, that is, patients receiving antidiabetic medications had longer survival time than untreated diabetic patients (MST: 135.8 months versus 80.2 months, p: 0.007), whereas the prognosis was greatly improved in colorectal cancer patients without diabetes mellitus (p <0.001). Medical treatment for hypertension and diabetes mellitus was associated with 28% (hazard ratio [HR]: 0.72; 95% confidence interval [CI]: 0.47-1.10; p: 0.131) and 57% (HR: 0.43; 95% CI: 0.22-0.82; p: 0.010) reduced risk of dying from colorectal cancer relative to those without medications, respectively. Our data indicate that long-term antidiabetic medications can significantly prolong the survival and improve the prognosis of post-surgical colorectal cancer.