Purpose <p>Folic acid (vitamin B9) plays a vital role in DNA synthesis, repair, and methylation, supporting both normal cellular functions and the proliferation of cancer cells. This review aims to explore the complex interplay between folic acid metabolism, antifolate chemotherapy (particularly methotrexate), and chemotherapy-induced malabsorption, with an emphasis on the need for nutritional interventions.</p> Methods <p>A comprehensive literature review was conducted using databases such as PubMed, Scopus, and Google Scholar to identify studies addressing folic acid deficiency, chemotherapy-related malabsorption, methotrexate toxicity, and nutritional support strategies in cancer patients.</p> Results <p>Evidence indicates that methotrexate-induced inhibition of dihydrofolate reductase disrupts folate pathways, contributing to folic acid deficiency and malabsorption syndromes. This can lead to clinical complications such as anaemia, mucositis, immune suppression, and reduced treatment tolerance. Nutritional deficiencies further exacerbate drug toxicity and impair patient outcomes. While folic acid supplementation has shown benefit in reducing toxicity, its dosing must be carefully managed to avoid interference with chemotherapeutic efficacy.</p> Conclusion <p>Folic acid deficiency and malabsorption are significant concerns in cancer therapy involving antifolate drugs. Targeted nutritional strategies, including judicious folic acid supplementation, are essential to improving patient outcomes and minimizing treatment-associated complications. Future clinical approaches should integrate personalized nutritional support alongside chemotherapy regimens.</p>