Abstract: Persulfate (PS)-mediated Fenton-like systems have become an important advanced oxidation technology for enhanced removal of emerging contaminants from complex water matrices because of their relatively wide pH applicability, tunable reactive species, and low iron-sludge production. This review summarizes recent advances in PS-mediated Fenton-like systems from four aspects: reaction mechanisms and core advantages, catalyst design and optimization, support construction and engineering potential, and environmental behavior and regulation strategies in the watershed–estuary continuum. The results show that radical (SO₄·^-, ·OH) and non-radical (¹O₂, electron transfer, and high-valent metal-oxo species) pathways coexist in PS-mediated Fenton-like systems, and that the electronic structure and coordination environment of catalysts can be directionally regulated through single-/dual-atom design and defect engineering. Transition-metal-based catalysts, biochar, natural minerals, catalytic membranes, and nanoconfined structures exhibit different activity, stability, and engineering compatibility under different application scenarios. In the watershed–estuary continuum, salinity, halides, dissolved organic matter, and alkalinity can alter reaction pathways and affect the formation risk of brominated by-products (Br-DBPs) and BrO₃^-. Finally, this review summarizes and discusses future research directions in this field, providing a theoretical basis for further research and engineering application of PS-mediated Fenton-like technology in emerging contaminant control and watershed–estuary water environment regulation.