Previous studies of pre-strain have mainly focused on the mechanical behavior of materials, whereas the tensile–compressive asymmetry in the tribological behavior of high-entropy alloys (HEAs) remains insufficiently understood. To elucidate the effect of this asymmetry on the tribological behavior of HEAs, this study systematically investigated the nanoindentation and nanoscratching responses of fcc FeCoCrNiCu HEAs subjected to 5%, 7%, and 10% tensile or compressive pre-strains, with 0% pre-strain as the control group, using molecular dynamics simulations. The simulations were conducted using the LAMMPS software platform, with the embedded atom method potential describing interatomic interactions. The nanoindentation results show that tensile pre-strain accelerates plastic deformation, substantially reducing the pop-in load from 180.22 to 9.57 nN at 10% tensile and effectively relieving stress concentration. By contrast, although compressive pre-strain also reduces the pop-in load, the load remains considerably higher than that under the corresponding tensile pre-strain, and severe load fluctuations during plastic deformation indicate unstable deformation. The nanoscratching results show that tensile pre-strain enhances the tribological performance of FeCoCrNiCu HEAs: at 10% tensile , the coefficient of friction decreases from 0.59 to 0.43, and the average number of worn atoms decreases sharply from 316.06 to 71.68, indicating the best tribological performance among all conditions. At compressive pre-strain levels of ≤ 7%, the average number of worn atoms is reduced, whereas 10% compressive pre-strain degrades performance, causing the coefficient of friction and the average number of worn atoms to increase markedly above those of the unstrained state. Microscopic analysis confirms that tensile pre-strain promotes dislocation evolution and drives plastic deformation deep into the matrix, forming a three-dimensional network structure and producing a uniform strain distribution. Conversely, compressive pre-strain confines deformation to the surface region of the HEAs beneath the indenter, leading to localized plastic deformation and stress concentration.