Real-time control (RTC) and sustainable drainage systems (SuDS) can be implemented simultaneously to enhance the performance of existing urban drainage systems (UDS). However, significant challenges arise when choosing the optimal locations due to hydraulic interactions between the different interventions and the high number of possible configurations. This paper presents a novel optimization–simulation framework to optimize the spatial allocation of flow control devices (FCDs) combined with SuDS for combined sewer overflow (CSO) spill mitigation within UDS. Optimal intervention schemes were identified by a genetic algorithm (GA), combining different numbers of FCDs installed in existing manholes with simplified SuDS implemented in different portions of the catchment. The methodology was tested on two case-study catchments with different characteristics to mitigate CSO spills during synthetic storm events. FCD-SuDS configurations were then validated during continuous rainfall series, resulting in CSO spill volumes reduction ranging between 11% and 45% compared to the baseline networks. The results demonstrate how the GA-based method can efficiently identify optimal placement schemes within UDS characterized by different distributions of in-pipe storage potential as well as hydrological responses to rainfall-runoff events, enhancing the combined benefits of the two decentralized solutions for mitigating CSO spills.