Drug-induced gingival enlargement (DIGE) is an abnormal overgrowth that may occur as a side effect in some patients when calcium channel blockers, immunosuppressants, or anticonvulsants are taken. The prevalence of DIGE was shown to be 70% for phenytoin (30% for other anticonvulsant medicines) and 50-80% for cyclosporine. The usage of these medications is increasing as new indications emerge. These drugs act through a common mechanism of action at the cellular level by inhibiting intracellular calcium influx. DIGE is characterized by the presence of varied quantities of inflammatory infiltrates, primarily plasma cells, and an excessive build-up of extracellular matrix like-collagen. Fibroblasts, the cells responsible for collagen synthesis, may become hyperactive, leading to the excessive production of collagen fibers. This increased collagen content can result in the enlargement of gingival tissues. As collagen deposits increase, it hinders normal oral care routines, masticatory processes, and esthetics. In this study, we compared the cytotoxicity of phenytoin, gabapentin, and cyclosporine on gingival fibroblast cells using the methyl thiazolyl-tetrazolium assay to understand their effect on gingival fibroblast cells. Phenytoin had the greatest half-maximal inhibitory concentration (IC50) with a value of 305.78 µg/ml, followed by gabapentin with a value of 260.44 µg/ml and cyclosporin with a value of 243.79 µg/ml. Understanding the cytotoxic thresholds of these medications is essential for improving patient outcomes and minimizing the incidence of gingival enlargement in those requiring long-term therapy. According to the study, cytotoxicity increases along with medication concentration. These findings will assist medical professionals in selecting the drug that poses the least risk of adverse effects on gingival health, ultimately guiding more informed prescribing practices.