Aircraft compression ignition (CI) engines, originally developed for ground applications, exhibit significant ignition problems due to various fuel compositions and reactivities encountered in the field. Energy addition via a hot surface ignition assistant is one potential remedy; however, its durability against harsh engine conditions should be bolstered. Analysis of the thermo-mechanical stress within the device during operation can provide useful inputs for design improvements and material selection. In the present study, the effect of several parameters (fuel injection pressure, hot surface temperature, and the vertical and horizontal location of hot surface tip) on the thermo-mechanical stress of an ignition assistant device during combustion events inside a rapid compression machine (RCM) was investigated using the design of experiments (DoE) analysis approach. For 37 cases sampled from our previous study, numerical experiments via transient thermo-mechanical finite element analysis (FEA) were carried out using the boundary conditions coupled from the computational fluid dynamics (CFD) results. A full quadratic response surface model was obtained from the DoE analysis. The relationship between the input parameters and the maximum stress of the ignition assistant was investigated and dominant factors were identified. In addition, the thermo-mechanical behavior of the ignition assistant in response to thermal shock imposed by cold fuel spray impingement was reviewed in detail for the case where the maximum stress was observed.