The performance of a three-dimensional electrochemical (3D-EC) system for degradation of tetracycline (TC) in aqueous solution was investigated within the framework of a three-factor, three-level Box Behnken (BBD) experimental design-based response surface methodology (RSM). Three independent variables (namely TC initial concentration ranging from 20 to 100 mg/L, pH ranging from 3.0 to 9.0, and current density (CD) ranging from 1.02 to 15.38 mA/cm(2)) were coded as A, B, and C at three levels (-1, 0, and 1), respectively. A second-order (quadratic) polynomial regression equation was developed to estimate responses. The significance of independent variables and their interactions were assessed using analysis of variance (ANOVA) at 95% confidence interval. The results of the statistical analysis demonstrated that three main effective factors and reactor performance were satisfactorily described by the derived quadratic polynomial model (R-2 = 0.87, F-value = 21.73, p-value < 0.0001). The model adequacy was further examined using residual plots. The results showed that the applied current density had a significant positive effect, while the initial pH imposed a negative effect, and the effect for TC was insignificantly negative. Based on the applied desirability function methodology, it could be possible to obtain a TC removal efficiency of 89.22% under optimum conditions for the present process-related variables (TC concentration = 28.9 mg/L, pH = 3.0, and CD = 15.38 mA/cm(2)).