Oral submucous fibrosis (OSMF), the most commonly encountered potentially premalignant oral epithelial lesion, is a chronic disorder associated with areca nut chewing. It has a relatively high potential for malignant transformation resulting into oral squamous cell carcinoma (OSCC), the most common oral malignancy with high mortality rate. Paymaster first described the malignant potential of OSMF in 1956, the rate of which had been estimated to be 7–13%. The pathogenesis of OSMF in itself is quite varied, and hence, its transformation to malignancy is also open to many varied mechanisms. The early diagnosis and sequentially, early treatment of OSMF is desirable so that the progression towards malignancy can be controlled. There are various theories that have been put forward explaining the probable pathway of malignant transformation of OSMF such as hypoxia, areca nut as a carcinogen or epithelial–mesenchymal transitions. Many recent molecular advances have also highlighted few biomarkers and genes that play a pivotal role in transformation of OSMF to OSCC. The purpose of this systematic review is to discuss all the possible mechanisms of malignant transformation of OSMF. Further research is still needed to establish the exact mechanism responsible for transformation of OSMF to OSCC and to reduce the mortality by newer interventions.