Background: This study was conducted to find out CD10 expression in premalignant and epithelial malignant lesions of the colon and rectum with clinicopathological correlation. Methods: This was a hospital-based cross-sectional study conducted 50 biopsy/resected specimens of adenomas (20 cases) and adenocarcinomas (30 cases) who were selected randomly. They underwent H&E staining and IHC for CD10, with the exclusion of non-epithelial tumor samples and submitted to the Department of Surgical Gastroenterology, Department of Surgery, Hi-Tech Medical College and Hospital, from August 2020 to August 2023, after obtaining clearance from the institutional ethics committee and written informed consent from the study participants. Results: Among the 50 cases, 35 (70%) >50 years and 15 (30%) <50 years, 28 (56%) were males, and 22 (44%) were females. Location-wise tumours comprise rectum 16 (32%), followed by descending colon 13 (26%), ascending colon 10 (20%), rectosigmoid junction 7 (14%), and transverse colon 4 (8%). The level of CD10 expression slowly rose from adenomas (<10%) to well-differentiated (G1)-adenocarcinomas (10–25%), with the highest level of expression seen in poorly differentiated (G3)-adenocarcinomas (>50%). Conclusion: At every step of the adenoma-carcinoma cascade, CD10 is crucial. Association of CD10 expression with malignant behaviour of colorectal adenocarcinomas and CD10 could be a new biomarker for aggressiveness and prognostic information. When used as a therapeutic target, CD10 will allow for the greatest possible targeting of malignant areas.