In this paper, the cook-off characteristics of NTO/HMX-based plastic-bonded explosives, here after referred to as JEO, with confined and pressure-relief structures are investigated. Firstly, a pre-ignition thermal decomposition model and a post-ignition combustion model of the explosives were established. The chemical reaction kinetics and combustion reaction parameters in the numerical model were calibrated according to a small closed-bomb experiment. The cook-off process of the explosives was then studied by numerical simulation, determining the influence of different structures on the ignition time, ignition position, and reaction intensity of a JEO charge. The cook-off of NTO/HMX-based plastic-bonded explosives with different structures was then experimentally studied, obtaining the temperature curve of each explosive, the deformation of the shell and liner, the macro-reaction phenomena when the charge was ignited and the residue state after the reaction, which verified the validity of the numerical simulation.