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This paper develops a control co-design (CCD) framework to simultaneously optimize the spacecraft’s trajectory and onboard system (rocket engine) and quantify its benefit. An open-loop optimal control problem (two-finite burn Mars missions) is used as the benchmark, and the engine design considers the combustion equilibrium and nozzle geometry. The objective function is the fuel burn. The design variables are the trajectory control parameters (such as burn times, burn directions, and time of flight), initial fuel mass, and engine design parameters (such as throat area, mixture ratio, and chamber pressure). The constraints include the final velocities and positions of spacecraft. Single-point optimizations are conducted for three departure dates in May, July, and September 2020. A multipoint optimization is also performed to balance the engine performance for these dates with 49 design variables and 20 constraints. It is found that the CCD optimizations exhibit 22–28% more fuel burn reduction than the trajectory-only optimization with fixed engine parameters and 16–20% more fuel burn reduction than the decoupled trajectory-engine optimization. The proposed CCD optimization framework can be extended to more spacecraft trajectory control parameters and onboard systems and has the potential to design more efficient spacecraft missions.