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 longterm antidiabetic medications can significantly prolong the survival and improve the prognosis of post-surgical colorectal cancer.