This study introduces an innovative in-situ heat-activated peroxymonosulfate (PMS) system as an efficient pretreatment strategy for mitigating biofouling in membrane distillation (MD) for seawater desalination. The system demonstrated robust microorganism inactivation in Red Sea seawater at MD operating temperatures of 60, 70, and 80 °C. This was attributed to the thermally accelerated generation of reactive chlorine species, achieving a log removal exceeding 3.6. The heat-activated PMS system significantly reduced the normalized vapor flux decline, by approximately 3.2 times at 60 °C (54 % vs. 17 %), 3.8 times at 70 °C (42 % vs. 11 %), and 5.7 times at 80 °C (56 % vs. 9.9 %), at a volume concentration factor of 4, compared to untreated system. These improvements were validated by optical coherence tomography imaging, which confirmed suppressed biofilm formation on the MD membrane surface, and live cell analysis, confirming a substantial decrease in live bacterial cell deposition. These findings highlight the potential of the heat-activated PMS system as a sustainable and efficient in-situ pretreatment strategy capable of addressing biofouling challenges and enhancing MD performance, offering a practical and scalable solution for seawater desalination applications.