In this study, the fretting wear test was performed on DD6 single-crystal superalloy after femtosecond laser modification (FLM) to evaluate the influence of femtosecond laser-induced asperity and hardened layer on its fretting regime. Results show that the ablation layer with a depth of similar to 3.2 mu m and the deformed layer are formed beneath the surface, with an increase in surface roughness and hardness. The ablation layer is composed of Al2O3, Cr2O3, and spinel structures. However, the diffraction peak and near-surface orientation after FLM remain similar to those in DD6 single-crystal superalloy substrate, indicating that no remarkable phase change and recrystallization occur despite thermal effect during FLM. The hardened layer has lower plasticity, and the asperities are easy to remove, which results in material removal predominating during the friction process. Therefore, the asperity and hardened layer induced by femtosecond laser could change the fretting regime of DD6 single-crystal superalloy from mixed slip regime (MSR) to gross slip regime (GSR). FLM provides a possibility to replace crack initiation with acceptable material removal in special conditions.