This article presents a failure analysis and simulation of a heavy-duty engine crankshaft. The study includes macroscopic and microscopic structure observations, fracture analysis, abrasive wear analysis, crankshaft simulation modeling, and response surface optimization. Visual inspection reveals that the crankshaft fracture occurs at the transitional fillet of the crankpin. Microscopic observation of the fracture shows inclusions, crack propagation along strip-like sulfide and banded structures, making it prone to fatigue crack initiation. It is also observed that impurities such as sludge adhere to the surface of iron-based abrasive particles, which will destroy the flatness and continuity of the lubricating oil film and hinder the flow of lubricating oil, reduce the bearing capacity of the oil film and aggravate the crankshaft wear. Simulation results demonstrate that the maximum stress occurs at the transitional fillet of the crankpin, in the region where crack initiation takes place. Through the application of response surface optimization, the maximum stress value is reduced by 11.07%, and the maximum deformation is reduced by 10.50%. This method allows for rapid and effective optimization of the crankshaft structure, thereby improving its strength and reliability. The results indicate that the primary cause of premature crankshaft failure is fatigue fracture at the transitional fillet.