Background/Objectives: Thalassemia, a hereditary blood disorder, leads to reduced hemoglobin levels, impairing oxygen transport and negatively impacting patient health. Recent research suggests a possible association between thalassemia and gastrointestinal (GI) symptoms, such as abdominal pain, diarrhea, and GI bleeding, potentially due to immune compromise and iron overload. This systematic review aims to explore the prevalence and underlying factors of GI pathologies in thalassemia patients, excluding treatment-related effects and iron overload. Methods: A comprehensive search following the PRISMA guidelines was conducted to identify the prevalence and causes of GI disorders in thalassemia patients. Studies assessing non-treatment-related GI symptoms and their links to thalassemia were analyzed. After screening 1902 studies, 13 were included to investigate gastrointestinal manifestations in thalassemia patients. Results: Evidence indicates potential associations between thalassemia and GI disorders, including malabsorption, inflammatory bowel disease, Heliobacter pylori (H. pylori) infection, and celiac disease. Findings highlight immune compromise and iron dysregulation as possible contributing factors. Conclusions: This review highlights the importance of further research into the GI manifestations of thalassemia to enable early detection and improve patient health outcomes and quality of life. Addressing this gap may provide insights into better clinical management strategies for thalassemia patients.