We investigated the influence of the flake thickness for molybdenum disulfide (MoS2) field effect transistors on the effect of a 150 keV high-energy proton beam applied on these devices. The electrical characteristics of the devices with channel thicknesses ranging from monolayer to bulk were measured before and after proton irradiation with a proton fluence of 5 × 1014 cm-2. The subthreshold swing (SS), threshold voltage shift and electron mobility were extracted with the Y-function method after proton irradiation and significant degradation were observed. It is found that, with the increase of layer thickness, mobility degradation and threshold voltage shift both eased, but the SS degradation was insensitive to the MoS2 flake thickness increase. We also demonstrate that the threshold voltage shift is dominated by oxide charges; however, the mobility and SS degradations are mainly affected by the interface traps. Our study will enhance the understanding of the influence of high-energy particles on MoS2-based nano-electronic devices. By increasing the MoS2 flake thickness to a certain extent, one can hopefully find a balance between effectively resisting [Formula: see text] shift and achieving high mobility and small SS degradation.