This study aims to assess the efficiency of two natural-based coagulants, namely calcium lactate and tannic acid, and compare them with conventional coagulants, including polyaluminium chloride (PACl) and ferric chloride. Jar test experiments were performed on the raw inlet water of the Isfahan water treatment plant (IWTP) in Iran. Response surface methodology was implemented to design and optimize the experiments. The factors considered in the design were coagulant dose, pH, initial turbidity, and temperature. Results showed the acceptable efficiency of natural coagulants in turbidity reduction, so that they meet the potable standard levels. The final water turbidity in the optimum condition for calcium lactate, tannic acid, PACl, and ferric chloride were 0.58, 0.63, 0.56, and 0.76 NTU, respectively. The comparison between the performances of the coagulants showed no significant difference in turbidity removal. However, the sludge volume produced as well as the impact on pH alteration after coagulation–flocculation were lower when using natural coagulants than with conventional coagulants. Also, the residual aluminum for PACl measured was higher than the desired limit according to Iran's drinking water standard. Finally, the simple additive weighting method was used to rank the four coagulants based on the selected criteria. The results showed that the natural coagulants could be preferable to the conventional coagulants if the concerns regarding disinfection by-product formation due to their residual organics were resolved. Since this issue was fixed in the IWTP due to the ozonation process, calcium lactate was proposed as an efficient alternative to PACl.