This study proposes a high-recovery seawater desalination strategy that integrates a heat-activated peroxymonosulfate (PMS) pretreatment with RO–MD hybrid operations. Under Cl-rich seawater conditions, the heat-activated PMS pretreatment thermally promotes the formation of reactive chlorine species (RCS), enabling selective degradation of humic substances, which are the dominant precursors of organic fouling. In synthetic seawater, the heat-activated PMS pretreatment achieved up to 44.5% removal of total organic carbon (TOC) at 2 mM PMS and 90 °C. Experiments using real Red Sea water demonstrated 30% TOC reduction with >90% removal of the humic substance fraction, reflecting the preferential cleavage of high-molecular-weight organics into low-molecular-weight species. This selective degradation substantially mitigated organic fouling in RO, maintaining 48% of the initial flux at 50% recovery, compared with 34% without pretreatment. The subsequent MD process with heat-activated PMS pretreatment increased the achievable volume concentration factor (VCF) from 2.5 to 3.3 (overall water recovery of approximately 85%), while markedly suppressing both NaCl and CaSO4 scaling. The improved MD performance arises from the prevention of organic–inorganic composite scale formation. Therefore, the integration of the heat-activated PMS pretreatment with RO–MD desalination provides a potential strategy for achieving high-recovery seawater desalination.