The behavior of lithium-ion batteries (LIBs) under mechanical loading is a complex multiphysics process including mechanical deformation, internal short circuit, and thermal runaway. To deeply understand the mechanism of battery failure and accurately predict the onset of internal short circuit and thermal runaway, a multiphysics-based computation framework of LIBs is in pressing need. In this article, a multiphysics model that couples five submodels (mechanical model, internal short-circuit model, battery model, heat transfer model, and thermal runaway model) is established to predict the evolution of force, voltage, and temperature under steel ball compression. The suitable agreement between simulation results and experimental data of batteries with different state of charges demonstrates that the proposed model is capable of predicting the multiphysical behavior of the battery. Further, a systematic parametric study is conducted to investigate the short-circuit triggering and temperature rise of batteries under different conditions, and the workflow of battery safety optimal design is proposed by applying the multiphysics model.