Two-dimensional (2D) materials have exceptional mechanical properties that are absent in conventional bulk materials due to their ultra-thin structure with ultra-high surface-to-volume ratio. Despite their great potential both for basic research and applications, however, deep understanding of fundamentally important orientation-dependent mechanical responses of 2D materials have rarely been achieved. In this work, for the first time, we investigate the tensile mechanical response of 2D transition-metal carbides (MXenes) as gradually varying tensile direction by using reactive molecular dynamics simulations. Despite its highly bonded multi-atom-thick structure, MXene proves significantly stretchable (11–17%) for all directions with isotropic stiffness desirable for flexible/wearable applications, while exhibiting unusual characteristic fracture anisotropy. Noticeably, these mechanical features remained qualitatively the same regardless of presence/absence of surface termination. We discover that MXene has always fractured into zigzag-atomic edged fragments regardless of tensile direction and/or surface termination. We reveal the detailed fracture mechanism and propose its generalization to other hexagonal 2D materials with validation for both pristine and surface-hydrogenated graphene nanosheets. Based on these findings, we finally present a physically robust, computationally efficient framework for fast and reliable prediction of MXenes’ unique fracture anisotropy, showing excellent agreement with time-consuming simulation results and suggesting broad applicability to 2D material mechanics.