A damage tolerance test of the metal-composite connection structure with initial damage was conducted for the composite skin-metal skeleton structure used in the reusable launch vehicle, and a damage tolerance performance prediction model of the corresponding structure was created. The research results show that metal structures containing initial cracks at the edge of the connection hole will undergo crack expansion under fatigue load. Due to the geometric asymmetry of the connection structure, the crack expansion rates on the upper and lower surfaces are inconsistent, resulting in crack observation from the outer surface causing an error in the damage size. Extrusion load causes some delamination expansion in composite laminates with preset delaminations; extrusion fatigue damage to the composite materials is the primary cause of the damage. Delamination around composite connection holes will drastically reduce the life of the metal-composite connection structure. The damage tolerance design of the metal-composite connection structure should focus on composite hole edge delamination damage. The prediction results of the established metal-composite structure damage tolerance performance prediction model are in good agreement with the test results. It can well predict the damage expansion process and extended life of the structure, and can be used to guide the damage tolerance design of this type of structure.