Oral potentially malignant diseases (OPMDs) are a group of oral mucosal lesions that have a higher chance of turning into cancer. They show up in different ways, have different causes, and look differently on a microscopic level. To date, there are no clinical or histological factors that could predict the OPMDs’ malignant transformation to oral squamous cell carcinoma (OSCC), except for previous OSCC and WHO classification. Early diagnosis appears to be essential in these lesions in order to identify the risk of malignant progression and treat them accordingly. The standard treatment for an oral precancerous lesion is surgical resection, which aims to remove all the affected epithelium. Despite the complete surgical removal of the lesion, there is a high probability of recurrence and the development of malignant transformation or a second tumor, based on the theory of “field of cancerization”. Researchers have developed the concept of chemoprevention, which involves using a systemic agent to halt the carcinogenesis process, in an attempt to minimize the probability of recurrence. Researchers have conducted several unsuccessful studies analysing retinoic acid, beta-carotene, vitamin C, the OX-containing oral rinse, and erlotinib. Following these negative results, we conducted a deeper analysis to investigate the peri- and intratumoral immune activity. Studies have demonstrated that changes in the number of tumor infiltrating CD8+, CD3+, and Th1 cells can influence the malignant transformation of OPMDs. Researchers also demonstrated high expression of PD-L1 in those premalignant lesions that progress to cancer. So, an imbalance in the immunosuppressive microenvironment could be the key to turning a premalignant cell into a cancerous cell, which suggests that immunotherapy could be useful as a drug for prevention. Glenn J. Hanna et al. conducted the first study to investigate the effectiveness of immune checkpoint inhibitors in this setting, treating 33 patients with proliferative verrucous leukoplakia with 4 cycles of nivolumab. They showed different levels of lesion regression depending on the size and degree of dysplasia in response to treatment. However, 27% of patients who received nivolumab went on to develop invasive oral cancer, with a 73% cancer-free survival rate after 2 years. Currently, another phase II study, called “IMPEDE trial”, is ongoing that aims to analyse the role of avelumab against malignant transformation in patients with oral premalignant lesions which have any grade of dysplasia and are positive for loss of heterozygosity (LOH). Although these early results on the use of immune checkpoint inhibitors to reverse the malignant transformation of OPDMs are promising, there are many open questions still to be clarified. Fundamental is the need to have randomized trials with long-term outcomes.