The orientation between twin boundary (TB) and loading direction may play an intriguing role in the deformation behaviors of twinned metallic materials. In this aspect, its essential effect on the high-entropy alloy (HEA) nanocrystals is elusive. Attention herein is focused on the atomic-scaled deformation mechanisms and fracture behaviors of HEA nanocrystals containing twins of even smaller spacings via a combined approach of in situ tensile tests inside a high-resolution transmission electron microscope and molecular dynamics simulations. The results indicate that the deformation mechanisms (especially dislocation activities) of HEA nanocrystals depend on the load orientation with respect to TBs. Because of the low activation energy and uneven local composition of HEA, the surface acts as an effective dislocation source and, together with Schmid factor, dominate the activated dislocation slip system. The load orientation-dependent TB-dislocation interactions may transform the type of fracture from semi-brittle to ductile. Our results indicate that the deformation mechanisms and the types of fracture in HEA nanocrystals can be controlled by changing the orientation.