Background: Glutathione peroxidases are major antioxidant molecules, involved in redox homeostasis in cancer cells and cancer stem cells (CSCs). Cancer stem cells are implicated in tumor progression, recurrence, and therapy resistance. Aim: This study aims to evaluate the prognostic value of glutathione peroxidase2 (GPx2) and the stem cell-related marker (SOX2) immunohistochemical expression in relation to survival in colonic carcinoma patients. Patients and Methods: GPx2 and SOX2 immunohistochemical expressions were assessed in 85 cases of stage II and III colonic carcinomas and their relation to the clinicopathologic parameters and patients' survival was evaluated. Results: High GPx2 expression was detected in 51.8% of cases, while only 25.9% of cases showed high SOX2 expression. GPx2 expression was significantly related to tumor grade, lymph node status, pathological tumor stage, lymphovascular invasion, as well as perineural infiltration. High SOX2 expression was significantly associated with tumor grade, lymph node invasion, pathological stage, and lymphovascular invasion. A significant relation was also detected between GPx2 and SOX2 expression. Both high GPx2 and high SOX2 were significantly related to poor overall survival (OS) and disease-free survival (DFS). Conclusions: High expression of GPx2 and SOX2 in colonic carcinoma is associated with features of aggressive tumor behavior, including poor tumor differentiation, lymph nodal status, advanced stage, lymphovascular invasion, and poor patients' survival. Additionally, the expression of GPx2 in colonic carcinoma was significantly related to SOX2 expression. These markers can be considered prognostic markers for colonic carcinoma.