Background Colorectal carcinoma (CRC) is the third most common cancer in the world. Human class I homeobox A13 (HOXA13) was initially identified as a transcription factor and has an important role in embryonic development and malignant transformation. Mammalian STE20-like kinase 1 (STK4/MST1) encodes a serine/threonine kinase that is the mammalian homolog of the Hippo pathway and plays an important role in controlling cell growth, apoptosis, and organ size. Aim This work aimed to evaluate the role of HOXA13 and STK4/MST1 in conventional colorectal adenoma and adenocarcinoma. Materials and methods This retrospective study was carried out on 20 cases of conventional colorectal adenoma and 30 cases of conventional colorectal adenocarcinoma. HOXA13 and STK4/MST1 immunostaining was done and assessed for each case. Correlation with the clinicopathological findings and statistical analysis was studied. Results In the carcinoma cases, there was a highly significant direct statistical correlation between HOXA13 expression and tumor grade, lymph node metastasis, and TNM stage (P<0.01 for each). Inverse statistical correlation between STK4/MST1 expression and tumor grade, depth of tumor invasion (T), and TNM stage (P<0.01 for each) was found. HOXA13 and STK4/MST1 immunoexpression showed direct highly significant relation with the transition from adenoma to adenoma with dysplasia to adenocarcinoma (P<0.01). There was a highly significant inverse statistical correlation between HOXA13 and STK4/MST1 expression in the studied cases of CRC (P<0.01). According to receiver-operating characteristic curve, both markers were good in the prediction of metastatic potential in the carcinoma cases using the TNM stage as a parameter with a sensitivity of 85%. Conclusion HOXA13 was immunohistochemically overexpressed, while STK4/MST1 was downexpressed in progression from colorectal adenoma to adenoma with dysplasia to adenocarcinoma cases. HOXA13 and STK4/MST1 might have a potential role as independent prognostic factors in CRC and may have validity to predict metastatic potential of CRC.