The persistent environmental contamination and toxicity of perfluorooctanoic acid (PFOA) necessitate adsorbents that combine high capacity, fast kinetics, and robust recyclability. Metal–organic frameworks (MOFs) offer tunable porosity and functionality, yet integrating these attributes into a single material remains challenging. Here, we demonstrate that MOF-818, a mesoporous MOF featuring two distinct secondary building units (Zr6 and Cu3 clusters) with abundant open metal sites (OMSs), achieves exceptionally efficient PFOA removal via a synergistic adsorption mechanism. The OMSs enable strong chemisorption of PFOA carboxylate groups, while the hierarchical mesopores (3.8 nm) facilitate rapid diffusion and subsequent physisorption of PFOA chains. This synergy yields an adsorption equilibrium within 5 minutes and a high capacity of 1.51 g g−1 (3.65 mmol g−1), with effective removal even at trace concentrations (from 250 μg L−1 to ∼15 μg L−1). MOF-818 also exhibits excellent selectivity against common coexisting ions and retains 97% of its capacity after eight regeneration cycles. Combined experimental and computational analyses confirm that chemisorption at OMSs initiates the process and enables subsequent physisorption. This work highlights the power of engineering dual adsorption modes within a single MOF platform as a superior strategy for rapid and high-capacity remediation of per- and polyfluoroalkyl substances (PFAS).