Quantum key distribution (QKD) technology can create unconditional security keys between communication parties, but its key generation rate can’t satisfy high-speed network applications. As an essential part of QKD system, the design of post-processing system has a huge influence on its key generation rate. For the challenges of real-time and high-speed processing requirements, we propose a pipeline optimization model for QKD post-processing system. With the variable granularity division policies in our model, a high-speed pipeline QKD post-processing system can be designed with the constraints of limited computing and storage resources and security requirements. Simulation results show that for GHz BB84 protocol based QKD system, the security key generation rate of our post-processing system can reach to 600kbps with 25km distance. We believe that our work can provide useful guidance for the design of future QKD system.