Materials can suffer mechanical fatigue when subjected to cyclic loading at stress levels much lower than the ultimate tensile strength, and understanding this behaviour is critical to evaluating long-term dynamic reliability. The fatigue life and damage mechanisms of two-dimensional (2D) materials, of interest for mechanical and electronic applications, are currently unknown. Here, we present a fatigue study of freestanding 2D materials, specifically graphene and graphene oxide (GO). Using atomic force microscopy, monolayer and few-layer graphene were found to exhibit a fatigue life of more than 109 cycles at a mean stress of 71 GPa and a stress range of 5.6 GPa, higher than any material reported so far. Fatigue failure in monolayer graphene is global and catastrophic without progressive damage, while molecular dynamics simulations reveal this is preceded by stress-mediated bond reconfigurations near defective sites. Conversely, functional groups in GO impart a local and progressive fatigue damage mechanism. This study not only provides fundamental insights into the fatigue enhancement behaviour of graphene-embedded nanocomposites, but also serves as a starting point for the dynamic reliability evaluation of other 2D materials.