Motivated by the need for enhancing sorbent affinity for per- and polyfluoroalkyl substances (PFAS), we demonstrate the possibility of rationally designing clay-based material (FluoroClay) with a pre-selected intercalant and predicting sorbent performance using all-atom molecular dynamics simulation coupled with density functional theory-based computation. Perfluorohexyldodecane quaternary ammonium (F6H12A) as the selected intercalant revealed significant enhancement in adsorption affinity for hard-to-remove compounds, including perfluorobutane sulfonate (PFBS) and polyfluoroalkylethers (GenX and ADONA). The adsorption is thermodynamically entropy-driven and dominated by the hydrophobic effect. The incorporation of fluorine atoms into clay intercalants gave rise to a hydrophobic and fluorophilic "cavity" structure for targeted PFAS. The self-assembly of intercalant-PFAS under the negative electric field of clay sheets created a unique configuration that significantly enlarged the contact surface area between PFAS and F6H12A and was quantitatively driven by their intermolecular interactions, e.g., CF chain-CH chain, CF chain-CF chain, and charge-CH chain interactions. Collectively, our work demonstrated a new approach to select fluorinated functionality for designing a new adsorbent and estimating its performance via molecular simulation. It also provided an in-depth understanding of the underlying fundamental physics and chemistry in the adsorption of PFAS, suggesting a new strategy for PFAS removal, particularly for short-chain PFAS and new chemical alternatives.