We used an experimental design to determine the best coagulation–flocculation mechanism and the optimal operating conditions for the maximum removal of the natural organic matter fractions (hydrophobic acid (HPOA) and hydrophilic neutral (HPIN)), which are the main factors responsible for irreversible membrane fouling and the generation of disinfection by-products (DBPs). Charge neutralization and sweep mechanisms (SM) were studied using the jar test experiment, and synthetic waters prepared with different hydrophobic/hydrophilic (HPO/HPI) weight ratios by adding model compounds to represent the dissolved organic matter (DOM) fractions. Significant influence factors were identified for both coagulation mechanisms. The SM was the best one for DOM removal independent of the HPO/HPI weight ratio. The SM removed HPOA and HPIN fractions with efficiencies of 87.5–90.5% and 73.6–89.8%, respectively. The dissolved organic carbon (DOC) values of all met the recommendation proposed by the United States Environmental Protection Agency (2 mg total organic carbon (TOC)/L or 1.8 mg DOC/L) for DBPs (<100 μg/L). Furthermore, all effluents met the DOC and silt density index recommended values by membrane suppliers (<3 mg DOC/L and <5%/min, respectively) to minimize fouling potential and to extend the membrane life.