Perfluorooctanoic acid (PFOA) substitutes such as hexafluoropropylene oxide dimer acid (GenX) and hexafluoropropylene oxide trimer acid (HFPO-TA) are toxic as environmental contaminants, and efficient adsorbents are required to remove them from waters. In this study, the novel cationic covalent organic framework (COF) was developed via an imine condensation reaction for efficient removal of GenX and HFPO-TA from aqueous solution. The prepared COFs exhibited a 2D ordering hexagonal structure with AA stacking and two classes of pores (mesopore and micropore). The introduction of quaternary ammonium on COF exhibited little effect on its morphology and crystal structure. The cationic COF with quaternary ammonium showed high adsorption capacity for GenX (2.06 mmol/g) and HFPO-TA (2.16 mmol/g), more efficient than conventional activated carbons and resins. The effects of pH and natural organic matter on the removal efficiency of GenX and HFPO-TA on COF were also investigated. Interestingly, the previously adsorbed GenX on the cationic COF was replaced by the longer-chain HFPO-TA, and the underlying competitive mechanism was further clarified by performing a density functional theory calculation. This study highlights the exceptional potential of COFs through topology structural design for the efficient removal of per- and polyfluoroalkyl substances from aqueous solution.