Introduction Gastrointestinal tract (GIT) endoscopy with biopsy is essential for diagnosing and managing various GIT diseases, including malignancies and inflammatory conditions. This study aimed to analyze the spectrum of histopathological lesions in the GIT and their correlation with the endoscopic findings. Methodology This retrospective observational study was conducted at a tertiary medical college involving 114 patients who underwent GIT endoscopy between June 2023 and June 2024. This study focused on lesion types across different GIT sites (esophagus, stomach, and duodenum) and the agreement between endoscopic and histological diagnoses. Results Lesions were most prevalent in the stomach (52.6% of cases, n=60), followed by the duodenum (35.1%, n=40) and esophagus (12.3%, n=14). Significant correlations were found between endoscopic and histological diagnoses in the esophagus (concordance for esophagitis was 100%) and stomach (concordance for gastritis was 95%). In the duodenum, the concordance was high for duodenitis (100%) but lower for other lesions such as neuroendocrine tumors (71.43%). However, Cohen's kappa values indicated poor overall agreement across all sites (κ=0.49), reflecting variability in diagnostic accuracy. Conclusion This study highlights the reliability of endoscopic procedures for diagnosing upper GIT lesions, particularly in the esophagus and stomach, while emphasizing the challenges in diagnosing duodenal lesions. These findings support the need for targeted screening and further research to enhance diagnostic accuracy and patient outcomes in GIT diseases.