This study investigates the effects of environmental parameters such as UV intensity (X-1, 2.1 similar to 6.3 mW/cm(2)), Fe(III) (X-2, 0 similar to 0.94 mg/L), NO3- (X-3, 0 similar to 20 mg/L) and humic acid (X-4, 0 similar to 30 mg/L) on the removal efficiency of diclofenac (DCF, Y), and optimization using a response surface methodology (RSM) based on Box-Behnken design (BBD). According to analysis of variance and t-test results (p < 0.001), the proposed quadratic BBD model based on a total of 29 experimental runs fitted well to the experimental data. Moreover, the determination coefficient (R-2 = 0.990) and adjusted determination coefficient (R-a(2) = 0.981) indicated that this model is adequate with a high goodness-of-fit. Variables of X-1, X-2 and X-3 had significant positive contributions (p < 0.001), while X-4 had significant negative contribution to the DCF removal (p < 0.001). A Pareto analysis showed that X-4 was the most important factor (57.18%) in DCF photolytic removal. The predicted and observed DCF removal were 94.98 and 94.2% under optimal conditions (X-1 = 6.29 mW/cm(2), X-2 = 0.75 mg/L, X-3 = 15.65 mg/L and X-4 = zero), respectively. The RSM not only gives valuable information on the interactions between these photoreactive species (UV intensity, Fe(III), NO3-, and humic acid) that influence DCF removal, but also identifies the optimal conditions for effective DCF removal in water.