Green infrastructure (GI) has been regarded as an effective intervention for urban runoff reduction. Despite the growing interest in GI, the technical knowledge that is needed to demonstrate their advantages, cost, and performance in reducing runoff and pollutants is still under research. The present paper describes a framework that aims to obtain the optimal configuration of GI (i.e., the optimal number of units distributed within the catchment) for urban runoff reduction. The research includes an assessment of the performance of GI measures dealing with pollution load, peak runoff, and flood volume reduction. The methodological framework developed includes: (1) data input, (2) GI selection and placement, (3) hydraulic and water quality modelling, and (4) assessing optimal GI measures. The framework was applied in a highly urbanized catchment in Cali, Colombia. The results suggest that if the type of GI measure and its number of units are taken into account within the optimisation process, it is possible to achieve optimal solutions to reduce the proposed reduction objectives with a lower investment cost. In addition, the results also indicate a pollution load, peak runoff, and flood volume reduction for different return periods of at least 33%, 28%, and 60%, respectively. This approach could assist water managers and their stakeholders to assess the trade-offs between different GI.