Background: Colonoscopic biopsy remains a cornerstone for diagnosing colorectal diseases that range from inflammatory to neoplastic lesions. Understanding the histopathological spectrum of these lesions helps correlate clinical and endoscopic findings, guiding effective management strategies. Objective: To evaluate the spectrum and frequency of histopathological lesions in colonoscopic biopsies over a two-year period. Materials and Methods: This retrospective observational study was conducted in the Department of Pathology over two years (May 2023–May 2025). A total of 42 colonoscopic biopsy specimens were analyzed. All samples were processed, stained with Hematoxylin and Eosin, and examined microscopically. Lesions were classified into non-neoplastic and neoplastic categories based on the 2019 WHO classification of digestive system tumors. Data were analyzed using SPSS version 25.0. Results: Among 42 cases, non-neoplastic lesions constituted 74% and neoplastic lesions 26%. The most common non-neoplastic lesion was inflammatory bowel disease (38%), including ulcerative colitis (24%) and Crohn’s disease (14%), followed by chronic non-specific colitis (26%). Adenocarcinoma was the predominant neoplastic lesion (21%), with moderately differentiated types being most frequent. Lesions were most commonly located in the colon (54.8%) and rectum (41.9%). A male preponderance (M:F = 2:1) was observed, and most cases occurred in patients above 50 years. Conclusion: The study highlights that inflammatory bowel disease and adenocarcinoma are the most frequent histopathological findings in colonoscopic biopsies. Colonoscopic biopsy remains indispensable for early detection of inflammatory and malignant lesions, particularly in elderly males.