Due to the coexistence of multiple types of reservoir bodies and widely distributed aquifer support in karst carbonate reservoirs, it remains a great challenge to understand the reservoir flow dynamics based on traditional capacitance–resistance (CRM) models and Darcy’s percolation theory. To solve this issue, an improved injector–producer-pair-based CRM model coupling the effect of active aquifer support was first developed and combined with the newly-developed Stochastic Simplex Approximate Gradient (StoSAG) optimization algorithm for accurate inter-well connectivity estimation in a waterflood operation. The improved CRM–StoSAG workflow was further applied for real-time production optimization to find the optimal water injection rate at each control step by maximizing the net present value of production. The case study conducted for a typical karst reservoir indicated that the proposed workflow can provide good insight into complex multi-phase flow behaviors in karst carbonate reservoirs. Low connectivity coefficient and time delay constant most likely refer to active aquifer support through a high-permeable flow channel. Moreover, the injector–producer pair may be interconnected by complex fissure zones when both the connectivity coefficient and time delay constant are relatively large.