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<i>KRAS</i> mutation is a confirmed predictive biomarker for anti-EGFR monoclonal antibody therapy response for metastatic colorectal cancer. However, its prognosis impact and the predictive potential for first-line standard chemotherapy remains unclear. On the other hand, V600E mutation is the most frequent and studied mutation in the <i>BRAF</i> gene, and it has been associated with a poor outcome of patients and a low response to anti-EGFR treatment. Thus, the aim of this study is to evaluate the role of <i>KRAS</i> and <i>BRAF</i> mutations as prognosis factors and predictive biomarkers for 1st line standard chemotherapy in metastatic colorectal cancer. <i>KRAS</i> mutations and <i>BRAF</i> V600E mutations exhibited a poor outcome (<i>p</i> = 0.021 and <i>p</i> &lt; 0.0001, respectively). Cox multivariate analysis showed that the presence of liver metastasis (HR = 1.595; 95% CI: 1.086&#8722;2.343; <i>p</i> = 0.017), <i>KRAS</i> mutation (HR = 1.643; 95% CI: 1.110&#8722;2.431; <i>p</i> = 0.013) and <i>BRAF</i> V600E mutation (HR = 5.861; 95% CI: 2.531&#8722;13.570; <i>p</i> &lt; 0.0001) were statistically significant co-variables for progression-free survival. Interestingly, patients with <i>KRAS</i> mutations were associated with a poor response to first line standard chemotherapy (<i>p</i> = 0.008). In contrast, the <i>BRAF</i> V600E mutation did not have any impact on the first line standard chemotherapy response (<i>p</i> = 0.540). Therefore, in the present study, we provide new insight on the role of <i>KRAS</i> and <i>BRAF</i>, not only as prognosis biomarkers, but also as first line standard chemotherapy response biomarkers in metastatic colorectal cancer.