The present study aims to develop a practical approach for the optimal permeable reactive barrier (PRB) design towards Cr(VI) removal from groundwater. Batch and column experiments were performed to investigate the characteristics of the four proposed reactive materials; nanoscale zero-valent iron (Fe0), bimetallic nanoscale zero-valent iron (Fe0/Cu), activated carbon (AC) and sand/zeolite mixture (S/Z). Kinetic analysis and dynamic modeling of the experimental data were implemented to determine the controlling conditions of the reactive performance of the PRB's materials. The sensitivity index of the design parameters was examined as an indicator of their effect on the reactive responses. Moreover, the Response Surface Methodology (RSM) was considered for optimizing the design variables of the PRB based on the practical factorial analysis. Results revealed that Fe0 and Fe0/Cu showed high performance in Cr(VI) removal, with a slight superiority to Fe0, with final removal efficiency values of 89.7 and 84.1%, respectively. Kinetic analysis depicted that pseudo second order was the best fitting model for Cr(VI) removal in the four materials' cases. ANOVA statistical analysis revealed that quadratic polynomial model was the best model, corresponding to the highest correlation efficiency and adequate precision, to describe the relationships in the four PRB's cases between the selected dependent variables; resident time (tR), reactive material mass per sectional area of contaminant plume (M/A) and reactive material cost (CostPRB) towards the independent parameters; barrier thickness (b) and permeability (Kr). Additionally, sensitivity analysis has been conducted which depicted the high sensitivity, in the four PRB's cases, of average pore water velocity within the barrier (vr) vr and Kr with the highest and the second-highest sensitivity index (SI) values towards tR, respectively. The RSM-optimization revealed that Fe0 is the most feasible reactive material, comparing to the other considered materials, with respect to the optimal conditions regarding the long residency (tR = 22 days) and low cost (b = 0.521 m), with around 95.2% desirability of its optimal solution. Overall, the current study represents a significant contribution and a vital step towards an accurate PRB's design based on previously determined optimal conditions.