Uncertainty in determining optimum conjunctive water use lies not only on variability of hydrological cycle and climate but also on lack of adequate data and perfect knowledge about groundwater-surface water system interactions, errors in historic data and inherent variability of system parameters both in space and time. Simulation-optimization models are used for conjunctive water use management under uncertain conditions. However, direct application of such approach whereby all realizations are considered at every-iteration of the optimization process leads to a highly computational time-consuming optimization problem as the number of realizations increases. Hence, this study proposes a novel approach—a Retrospective Optimization Approximation (ROA) approach. In this approach, a simulation model was used to determine aquifer system responses (draw-downs) which were assembled as response matrices and incorporated in the optimization model (procedure) as coefficients in the constraints. The sample optimization sub-problems generated, were solved and analyzed through ROA-Active-Set procedure implemented under MATLAB code. The ROA-Active Set procedure solves and evaluates a sequence of sample path optimization sub-problems in an increasing number of realizations. The methodology was applied to a real-world conjunctive water use management problem found in Great Letaba River basin, South Africa. In the River basin, surface water source contributes 87% of the existing un-optimized total conjunctive water use withdrawal rate (6512.04 m3/day) and the remaining 13% is contributed by groundwater source. Through ROA approach, results indicate that the optimum percentages contribution of the surface and subsurface sources to the total water demand are 58% and 42% respectively. This implies that the existing percentage contribution can be increased or reduced by ±29% that is groundwater source can be increased by 29% while the surface water source contribution can be reduced by 29%. This reveals that the existing conjunctive water use practice is unsustainable wherein surface water system is overstressed while groundwater system is under-utilized. Through k-means sampling technique ROA-Active Set procedure was able to attain a converged maximum expected total optimum conjunctive water use withdrawal rate of 4.35 × 104 m3/day within a relatively few numbers of iterations (6 to 8 iterations) in about 2.30 Hrs. In conclusion, results demonstrated that ROA approach is capable of managing real-world regional aquifers sustainable conjunctive water use practice under hydro-geological uncertainty conditions.