Structural defects in two-dimensional (2D) materials are ubiquitous and can influence their physical and chemical properties. The presence of structural defects in single atom thick 2D materials such as graphene is detrimental to the tribological properties and is well documented; however, their effects on various other 2D materials such as transition metal dichalcogenides (TMDs) remain largely unexplored. Here, we report the role of wrinkles’ orientation on the nanoscale tribological behavior of the chemical vapor deposited (CVD) tungsten disulfide (WS2) monolayers. Our molecular dynamics (MD) simulations reveal the underlying atomistic mechanism which indicates the presence of wrinkles exhibiting various orientations, and maximum damage occurred when the tip moved at a 45-degree angle to the wrinkle. This underscores the significant influence of wrinkles’ orientation on the wear behavior of WS2 monolayers.