To investigate whether mutation profiling and microsatellite instability (MSI) status were associated with clinicopathological features and the prognosis in metastatic colorectal cancer (mCRC), mutations in RAS (including KRAS, NRAS, and HRAS) and BRAF were determined by Sanger sequencing. Tumor mismatch repair proteins and MSI status were examined using immunohistochemistry and polymerase chain reaction, respectively. The clinical value of these abnormalities was statistically analyzed, and prognostic value of different treatment regimens was also evaluated. Among 461 mCRC patients, mutations in RAS, BRAF, and MSI-high (MSI-H) status were observed in 45.3% (209/461), 5.6% (26/461), and 6.5% (30/461) of cases, respectively. Brain metastasis and high carcinoembryonic antigen level were highly correlated with KRAS mutation (P = 0.011 and P < 0.001), and tumors from females or located in the right colon tended to harbor BRAF mutation (P = 0.039 and P = 0.001). RAS/BRAF mutations may predict brain and/or lung metastases. Although neither clinical nor prognostic importance of MSI status was identified in our study, KRAS and BRAF mutations were demonstrated to be independent prognostic factors for overall survival and progression-free survival. Besides, in wild-type group, patients treated with chemotherapy plus targeted therapy exhibited the most favorable prognosis. Therefore, RAS/BRAF mutations may serve as indicators for prognosis and treatment options in mCRC.