Background: One of the biggest health issues in the globe is colorectal cancer (CRC). The third most common type of cancer to be diagnosed is colon cancer. Despite the many treatment approaches, there is a need to find novel prognostic and predictive indicators. EphA2, erythropoietin-producing hepatocellular receptor A2, is expressed to varying degrees in a variety of malignancies, including colorectal cancer, and may serve as a prognostic indicator and stage-specific marker. Objectives: To analyze the serum marker EphA2 level expression by enzyme-linked immune-sorbent assay (ELISA) in patients with CRC and assess its association with clinicopathological features, and patient survival. Patients and Methods: This study is a prospective study that included (80 cases) diagnosed with either cancer colon or rectal cancer, we selected patients who were diagnosed with primary colorectal cancer confirmed by histopathological diagnosis. Results: The patients in our study, 44 / 80 (55%) were diagnosed at stage IV, while the remaining 36 patients (45%) were diagnosed at stages II and III. Wild-type KRAS was present in 24 /41 patients (58.8%). The median overall survival (OS) for our patients was 21.3 months. We found a significant positive correlation between EphA2 levels and carcinoembryonic antigen (CEA) levels, with a P-value of 0.001. Additionally, EphA2 showed a highly significant relationship with the disease stage; higher EphA2 levels were associated with more advanced stages of the disease. While KRAS did not correlate with varying levels of EphA2, a correlation was observed between EphA2 levels and OS. Specifically, high EphA2 levels were associated with worse survival compared to the low EphA2 levels, with a P-value of 0.034. Conclusion: EphA2 serum level could be diagnostic and prognostic in CRC patients.  It might be included in the CRC panel for prediction and prognosis. This needs more studies with larger sample numbers.