A crosshead slipper-guide system, which bears a significant thrust force, is an essential friction pair in low-speed marine diesel engines. Owing to the low moving speed of the crosshead slipper during engine startup, it is difficult to form good hydrodynamic lubrication between the crosshead slipper and guide. Therefore, a detailed analysis of the crosshead slipper during engine startup is needed. In this study, a new transient tribo-dynamic model for a crosshead slipper during the engine startup process is presented. The model consists of a mixed lubrication model of the crosshead slipper-guide and dynamic models of the piston assembly, crosshead assembly, connecting rod, and crankshaft. The tribo-dynamic performances of the crosshead slipper during startup and under the rated conditions were simulated and compared. The results show that the tribo-dynamics of the crosshead slipper during the startup process are significantly different from those under the rated conditions. Some measures beneficial for the low friction of a crosshead slipper-guide under the rated conditions may significantly increase the friction loss of the crosshead slipper-guide system during the startup process.