This study evaluated the efficacy of 5-aminolevulinic acid photodynamic therapy (5-ALA-PDT) in 94 patients with oral potentially malignant disorders (OPMDs). Patients were treated with 20% 5-ALA and 635 nm laser light at 100 J/cm2 every 1-3 weeks, followed by at least 1 year of follow-up. Among the 94 patients, 36.2% achieved a complete response, with an overall response rate of 92.6%. Factors predicting better short-term efficacy included good oral hygiene (P = 0.042), no baseline pain (P = 0.025), single lesions (P = 0.025), lesion size <2 cm2 (P = 0.002), and the use of topical incubation (P = 0.004), particularly for ≥2.5 h (P = 0.002). With a median follow-up of 38 months, the cumulative recurrence rates were 33.0% at 1 year, 42.6% at 2 years, and the cumulative malignant transformation (MT) rates were 1.1% at 1 year, 10.6% at 2 years, and 25.5% at 5 years. Cox regression analysis identified female gender as an independent risk factor for recurrence. Hyperglycemia and lack of initial clinical response were independent predictors for MT. After 1:1 propensity score matching based on gender, age, and oral epithelial dysplasia grade, 84 pairs of patients were included in the PDT group and the control group. Kaplan-Meier survival analysis revealed that the matched control group showed faster MT (P = 0.041), especially among patients with lesions in high-risk areas (P = 0.001). The study indicates that 5-ALA-PDT is an effective treatment for OPMDs and may protect against malignant progression.