Response surface methodology (RSM) with central composite design (CCD) was used to monitor and optimize species-specific interaction of trihalomethane (THM) precursors in a scaled-up distribution network (DN). Independent variables such as applied chlorine (Cl2), contact time (t), humic acid (HA) and bromide ions (Br−) were analyzed using full factorial CCD. Analysis of variance revealed a good agreement between experimental data and proposed a two-factor interaction model (p = .04, R2 = 0.7983). As a precursor, Cl− and Br− interaction with HA affected THMs’ speciation. These precursor molecules were perceived least significant as discrete elements but HA: Br− and pH product significantly impacted total trihalomethane (TTHM) formation (r = 0.998, p = .007). This mutual interactive fraction was observed pH-dependent and influenced TTHM yield. Dibromochloromethane and bromoform formation was observed pH-dependent provided sufficient Br− in the system. Applied chlorine had significant (p = .01), while time had insignificant (p = .75) effect. Multiple response optimization suggested pH range between 6.0 and 7.6 and HA: Br− ratio between 1.3 and 5.9 were satisfactory for maintaining TTHM below ≤80 μg/L in DN with 0.88 desirability function (D). Their respective concentration may be minimized by changing precursor’s individual concentration and possible combinations