Knowledge of their bulk physical properties often guides selection of appropriate tribological coating materials. However, these properties as well as the microstructure evolve dramatically under the extreme conditions imposed during mechanical wear. The dynamic response ultimately governs the material’s wear performance; thus, understanding the dynamic evolution of the system is critical. This work characterizes the change in mechanical properties and microstructure as a function of wear cycles in model MoS2 films using a combination of nanowear testing, transmission electron microscopy, and site-specific nanopillar compression. Notably, mechanical wear enhances the mechanical properties of the MoS2 while simultaneously evolving a microstructure that reduces the coefficient of friction and wear rate. We hypothesize that this self-optimizing behavior underpins the exceptional lubricity and antiwear performance of MoS2.