This study was concerned with the mechanics and micromechanisms of diffuse (ultrastructural) damage occurrence in human tibial cortical bone specimens subjected to tension–tension fatigue. A nondestructive technique was developed for damage assessment on the surfaces of intact compact tension specimens using laser scanning confocal microscopy. Results indicated that diffuse damage initiates as a result of fractures in the inter-canalicular regions. Subsequent growth of those microscopic flaws demonstrated multiple deflections from their paths due to 3D spatial distribution of microscopic porosities (lacunae–canalicular porosities) and the stress-concentrating effects of lacunae. Damage dominating effects in the early stages of fatigue had been verified by the observed variations of the fracture toughness due to artificially induced amounts of damage. Toughening behavior was observed as a function of diffuse damage.