Background: Oral leukoplakia, a common oral potentially malignant disorder, carries a significant risk of transforming into oral squamous cell carcinoma (OSCC). Accurate prediction of this malignant transformation is critical for effective clinical management and improved patient outcomes. This study investigates the potential of molecular profiling to predict the malignant transformation of oral leukoplakia in a high-risk population. Methods: A retrospective cohort of 89 patients with oral leukoplakia was analyzed to identify key genetic alterations associated with the progression to OSCC. Genomic copy-number alterations and mutations in genes frequently linked to oral cancer, including TP53, FAT1, and NOTCH1, were examined. The presence of dysplasia was also incorporated into the analysis to develop a predictive model for malignant transformation. Results: Malignant transformation occurred in 28% of the cohort during follow-up. Notably, 89% of the oral leukoplakia lesions harbored at least one genetic alteration, with TP53 mutations present in 28% of cases. Copy number gains in chromosome region 8q24 and losses in 13q12 were also significantly associated with malignant transformation. The predictive model, integrating genetic and histopathological data, effectively stratified patients into distinct risk categories for malignant progression.