The studies on utilization of natural coagulants prepared from seeds of Citrullus lanatus (watermelon) and Cucumis melo (cantaloupe) provide insight on sewage wastewater treatment. The results were statistically analyzed by response surface methodology (RSM) based central composite design (CCD), and supported with results from Fourier Transform Infrared (FTIR) spectroscopy for functional groups present in coagulants. The batch coagulation studies were performed varying process parameters such as pH (5-7) and coagulant dosage (50-150 mg/L) at constant flocculant dosage of 10 mg/L using jar test. In jar test, coagulation was carried out with fast mixing (Mixing at 150 rpm for 1 min) followed by slow mixing (Mixing at 50 rpm for 30 min), and the final mixture was allowed to settle for 1 h at the temperature of 30±2ºC. Design-Expert® version 12 software was used to optimize pH and coagulant dosage for effective sewage wastewater treatment using natural coagulants with the objectives to maximize percentage reduction in turbidity, biological/biochemical oxygen demand (BOD), total suspended solids (TSS), and chemical oxygen demand (COD). The RSM results reveal that the optimum C. lanatus coagulant dosage of 72.3 mg/L at pH 5 achieved maximum efficacy removal of TSS and BOD by 92.8% and 92.1% respectively. The FTIR results show that the coagulants from plant seeds contain almost similar functional groups. Thus, it can be concluded that the coagulant prepared from C. lanatus would be more effective for treatment of sewage wastewater. © 2021, HARD Publishing Company. All rights reserved.