In this paper, a high-power low-speed diesel engine is studied, a multi-component coupling calculation and analysis model is developed, and transient dynamics and fatigue analysis software is applied to assess the body, crankshaft, and connecting rod for strength. The S-N curve of 42GrMoA material was measured utilizing a fatigue test, and the fatigue life of the body, crankshaft and connecting rod was determined. According to the experimental findings, the relative errors of stress calculation at the reference point of the crankshaft and connecting rod are 3.37% and 4.34%. In addition, this paper proposed a strength testing method incorporating multi-component coupling transient dynamic analysis and fatigue life calculation for low-speed diesel engines to accurately simulate the engine’s working process and consider the interaction between different components. This work provides method guidance and technical reference for the detailed fatigue analysis of high-power and low-speed engine block components.