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 wide pH adaptability, 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, carrier construction and engineering potential, and environmental behaviors and regulation strategies in the watershed-estuary continuum. The results show that radical (\mathrmSO_4 ^-\cdot, ·OH) and non-radical (¹O₂, electron transfer, high-valent metal-oxo species) pathways coexist in PS-mediated Fenton-like systems and can be selectively regulated via the coordination structure of active sites and defect engineering. Biochar, natural minerals, catalytic membranes, and nanoconfined carriers provide feasible engineering pathways for stable catalyst operation. PS-mediated Fenton-like systems should be deployed in terrestrial ex situ units such as advanced treatment of wastewater treatment plant (WWTP) effluents, enhanced treatment of industrial park effluents, and constructed wetland pre-reactors, to reduce pollution loads discharged into rivers and seas. In receiving waters, the gradients of salinity, halides, dissolved organic matter (DOM), and alkalinity govern reaction pathways and the yield of halogenated by-products. Meanwhile, sunlight, thermal stratification, suspended particulate matter, hydrodynamic disturbance, and microbial processes control pollutant transport and fate. Together, they provide the hydrochemical-hydrodynamic basis for siting and process configuration of upstream ex situ units. Future research should focus on addressing the challenges related to operational stability and environmental risk control in PS-mediated Fenton-like systems under complex aquatic conditions, advancing intelligent regulation, engineering applications, and hybrid treatment strategies, and establishing a watershed-marine collaborative governance framework for integrated land–sea environmental management.