Recent regulations on perfluorinated compounds in drinking water underscore the need for a deeper understanding of the formation of perfluorinated compounds from polyfluoroalkyl substances during chlorine disinfection. Among the compounds investigated in this study, N-(3-(dimethylaminopropan-1-yl)perfluoro-1-hexanesulfonamide (N-AP-FHxSA) underwent rapid transformation during chlorination. Within an hour, it produced quantitative yields of various poly- and per-fluorinated products, including perfluorohexanoic acid (PFHxA). Sixteen reactions involving chlorine with N-AP-FHxSA and its quaternary ammonium analog were investigated; seven were confirmed, while the remainder were either disproved or found to be insignificant. The quaternary ammonium moiety did not determine a polyfluoroalkyl substance’s reactivity toward chlorine. For example, while 6:2 fluorotelomer sulfonamide betaine transformed rapidly to PFHxA, other quaternary-ammonium-containing polyfluoroalkyl substances, such as 5:1:2 and 5:3 fluorotelomer betaines, showed significant resistance to chlorination. Further investigation identified potential sites for electrophilic attacks near the amine region by examining the highest occupied molecular orbitals of the polyfluoroalkyl substances. Visualization techniques helped pinpoint electron-deficient and electron-rich sites as potential targets for nucleophilic and electrophilic attacks, respectively. Increasing the solution pH from 6 to 10 did not diminish the apparent degradation of the studied polyfluoroalkyl substances, likely due to the greater reactivity of the deprotonated forms compared to the conjugate acids. Finally, we also examined the hydrolysis of polyfluoroalkyl substances at pH 6 to 11 in the absence of chlorine.