Nanoscale tribological behavior of Ni for its applications such as MEMS is an important area of study. The present study investigated the nanoscale friction and wear behavior of Ni on different crystallographic orientations using experiments and molecular dynamics simulations. Results showed an anisotropic friction response, with (100) [001] case showing high COF followed by (111) [1¯10] and (110) [1¯10] cases. Analysis showed that such a trend in COF is observed due to variation in activation of the number of slip systems in each case as determined by the Schmid factor calculations. Dislocation analysis showed that (100) [001] case developed the highest number of glissile dislocations which is attributed to high COF value. The wear volume followed an opposite trend of COF order, and the spatial distribution of displaced material is found to be different in each case, indicating an anisotropic ploughing mechanism. Such behavior is observed due to variations in the availability of the number of slip directions, their orientation on the scratch plane, and dislocation evolution during nanoscratch. Overall, this study provides insights into the complex deformation mechanism and wear behavior associated with scratch tests and has implications for the development of wear-resistant materials.