<p>Unlike perfluorinated compounds, the structural diversity of polyfluoroalkyl substances offers potential for degradation, yet their fate in conventional drinking-water treatment systems remains largely unexplored. To address this knowledge gap, we investigated the structure-dependent removal and transformation of cationic, zwitterionic, and anionic polyfluoroalkyl substances during rapid mixing (coagulation via alum), slow mixing (flocculation), and disinfection via chlorine. Coagulation and flocculation treatments resulted in an average removal of 34.7 ± 9.3% for cationic and zwitterionic polyfluoroalkyl substances and 44.2 ± 15.2% for anionic species from AFFF-contaminated water, as semi-quantified based on the mass spectrometric response. Non-target high-resolution mass spectrometry, assisted with Kendrick Mass Defect analyses, reveals a number of chlorination products and the transformation of polyfluoroalkyl substances to lower-molecular-weight intermediates. Electron-rich nitrogen enhanced chlorination rates, while electron-withdrawing groups like—SO₃H or –COOH slowed transformation due to reduced reactivity and steric hindrance. By building a quantitative structure−activity relationship model across representative polyfluroalkyl substances, we linked higher chlorine reactivity to the electrotopological state of the -NH- group in the non-fluorinated chain. Comparing chlorination kinetics in organic-free and pretreated surface water highlights the hindering impact of natural organic matter. A positive linear correlation was observed between the natural logarithm of the apparent transformation rate constants (ln<i>k</i>_obs) in organic-free water and those in surface water pretreated by coagulation and flocculation, with ln<i>k</i>_obs values averaging 1.75 times higher for cationic/zwitterionic substances and 1.93 times higher for anionic polyfluoroalkyl substances in organic-free water.</p>