Three-phase sequential turbocharging system with two unequal-size turbochargers is developed to improve fuel economy performance and reduce emission of the automotive diesel engine, which satisfies wide range of intake flow demand. However, it results in complicated transient control strategies under frequently changing operating conditions. The present work aims to optimize the control scheme of boost system and fuel injection and evaluate their contributions to the improvement of transient performance. A mean value model for diesel engine was built up in SIMULINK environment and verified by experiment for transient study. Then a mathematical model of optimization issue was established. Strategies of control valves and fuel injection for typical acceleration and loading processes are obtained by coupled calculating of the simulation model and optimization algorithm. Calculated result manifests that rapid augment of fuel supply enhances response characteristics of transient process initially and fuel injection is supposed to be decreased to avoid too much overshoot. During the transient condition, the switch-off turbocharger ought to be removed rapidly while the switch-on turbocharger should not be cut in until engine parameters are closed to target values. Experimental investigation of different control strategies was carried out. The calculated optimal control strategies of loading and acceleration process are effective to improve the transient performance. Reasonable boost strategy improves transient performance, but the influence of boost strategies on the loading process will diminish as the rise of engine speed. Transient switch boundaries need to be modified to achieve better transient performance in acceleration process.