Titanium alloy hot stamping technology has a wide range of application prospects in the field of titanium alloy part processing due to its high production efficiency and low manufacturing cost. However, the challenges of forming titanium alloy parts with large depths and deformations have restricted its development. In this study, the hot stamping process of a Ti6Al4V alloy box-shaped part was investigated using ABAQUS 2020 software. The thermodynamic properties of a Ti6Al4V alloy sheet were explored at different temperatures (400 °C, 500 °C, 600 °C, 700 °C, 800 °C) and different strain rates (0.1 s−1, 0.05 s−1, 0.01 s−1). In addition, the influence law of hot stamping process parameters on the minimum thickness of the formed part was revealed through the analysis of response surface methodology (RSM), ultimately obtaining the optimal combination of process parameters for Ti6Al4V alloy hot stamping. The experimental results of the hot stamping process exhibited a favorable correlation with the simulated outcomes, confirming the accuracy of the numerical simulation. The study on the microstructure evolution of the formed parts showed that grain refinement strengthening occurred in the part with large deformation, and the formed box-shaped parts exhibited a uniform and fine microstructure overall, demonstrating high forming quality. The achievements of the work provide important guidance for the fabrication of titanium alloy parts with large depths and deformations used in heavy industrial production.