Aim: This study aimed to evaluate the histomorphological spectrum of upper gastrointestinal (GI) lesions through endoscopic biopsies, analyze their distribution based on demographic and clinical parameters, and identify significant associations for improved diagnostic accuracy and management. Materials and Methods: This prospective study included 110 patients presenting with upper GI symptoms who underwent endoscopic biopsies. Detailed clinical histories, endoscopic findings, and histopathological evaluations were systematically recorded. Specimens were processed, stained with hematoxylin and eosin (H&E), and analyzed for non-neoplastic and neoplastic changes. Statistical analysis was performed using SPSS version 21.0, with a p-value <0.05 considered statistically significant. Results: Among 110 patients, 59.09% were male, with a mean age of 52.6 years. Dyspepsia (45.45%) and abdominal pain (22.73%) were the most common symptoms. Endoscopic findings revealed gastritis (36.36%) as the predominant lesion. Histopathological analysis showed non-neoplastic lesions (72.73%) as the most frequent, followed by benign neoplasms (13.64%) and malignant neoplasms (13.64%). Adenocarcinoma (53.33%) was the most common malignancy, followed by squamous cell carcinoma (26.67%). Conclusion: Endoscopic biopsy combined with histopathological evaluation remains a cornerstone in diagnosing upper GI lesions. Non-neoplastic lesions were predominant, with gastritis and esophagitis being the most common findings, while adenocarcinoma emerged as the leading malignancy. Early diagnosis through targeted endoscopy and histological analysis is essential for effective management and improved patient outcomes.