Elevated arsenic (As) contamination in water, especially groundwater, has been recognized as a major problem of catastrophic proportions. This work explores As(V) removal via the coagulation-flocculation process by use of ferric chloride coagulant and polyacrylamide k16 co-coagulant as a first time. The effects of major operating variables such as coagulant dosing (50, 125 and 200 mg/L), co-coagulant dosing (5, 12.5 and 20 mg/L), pH (6, 7and 8), fast mixing time (1, 2 and 3 min), and fast mixing speed (110, 200 and 300 rpm) on As(V) removal efficiency were investigated by a Box-Behnken statistical experiment design (BBD) and response surface methodology (RSM). According to factors F values, coagulant dosing, rapid mixing speed, pH, and co-coagulant dosing showed the most effect on As(V) removal efficiency, and the rapid mixing time factor indicated the slightest effect. The proposed quadratic model was significant with a p value < 0.0001 and has satisfactorily described the experimental data with R-2 and adjusted R-2 values of 0.9855 and 0.9738, respectively. Predicted model optimal conditions with target of complete As(V) removal were coagulant dosing = 197.63 ppm, co-coagulant dosing = 19.55 ppm, pH = 7.37, fast mixing time = 1.43 min and fast mixing speed = 286.77 rpm. The treatment of Nazarabad well water sample with an initial As(V) concentration of 5 mg/L under the optimal conditions removed 100% As(V) with the volume of produced sludge of 10.7 mL/200 mL. Increasing coagulant dosing, co-coagulant dosing, fast mixing time and fast mixing speed operation parameters from low-level to high-level values indicated 78%, 20%, 10.52% and 9.47% increases in volume of the produced sludge, respectively. However, a reduction of 13.63% in volume of the produced sludge resulted via pH increases.