Background Colorectal cancer (CRC) is one of the most frequent cancers worldwide. Cyclin D1 (CNND1) and cyclooxygenase-2 (Cox-2) are expressed in a plethora of neoplastic tissues. Aim The present work was conducted to examine the immunohistochemical expression of CNND1 and Cox-2 in colorectal adenocarcinoma, compared with colonic adenoma to evaluate its association with various clinicopathological features. Patients and methods A total of 30 colorectal adenocarcinoma cases, 20 cases of colonic adenoma, and 10 normal colonic mucosal biopsies as controls were studied. Immunohistochemical technique was applied to detect CNND1 and Cox-2 expression and correlate them with clinicopathological findings. Results Both cytoplasmic high CNND1 and nuclear positive Cox-2 expression were significantly increased from normal colonic mucosa (0 and 10%, respectively) to CRC (80 and 83.3%, respectively) passing through colon adenoma (25 and 55%, respectively) (P≤0.001 for both). High CNND1 score was significantly related to lymph node spread and stage (P≤0.001 for both). A statistically significant difference was documented between Cox-2 and grade of differentiation (P=0.017), distant metastasis, and TNM stage (P=0.033, 0.003, respectively). Conclusion The present work suggests the oncogenic role of CNND1 and Cox-2 in CRC. Furthermore, overexpressions of CNND1 and Cox-2 are associated with poor prognostic factors, implicating their potentially prognostic role in CRC.