Osteocytes, situated within the lacunocanalicular network (LCN) of the bone matrix, play crucial roles in sensing mechanical signals and orchestrating bone adaptive responses. Alterations in LCN structure could significantly modify the fluid dynamic microenvironment of osteocytes, thereby influencing bone mechanoresponses (BMRs). However, a comprehensive understanding of this tissue remains elusive. In this study, a multi-scale model of whole bone-LCN was developed to systematically investigate the effects of lacunocanalicular morphology (lacunar volume [Lc.V] and canalicular area [Ca.S]) and network architecture (lacunar density [Lc.ρ] and canalicular density [Ca.ρ]) on fluid shear stress (FSS) within the LCN and BMR predicted by fluid flow. Furthermore, the relationships between fluid flow within the LCN and BMRs were examined in two specific scenarios: aging and lactation. Results demonstrated that changes in lacunocanalicular morphology (Lc.V and Ca.S) primarily influenced the intensity of fluid flow, while alterations in the LCN (Lc.ρ and Ca.ρ) largely affected the distribution of fluid flow. Increases in Lc.V or decreases in Ca.S increased FSS, whereas decreases in Lc.ρ or increases in Ca.ρ reduced FSS. Compared with other structural parameters, alterations in Ca.ρ had the greatest effect on FSS, while BMR primarily depended on changes in Lc.V and Ca.S. In agreement with experimental observations, aging- or lactation-induced changes in LCN structure (and fluid dynamics) were associated with reduced (−50%) or increased (+20%) bone responses to mechanical loading, respectively. These findings suggest that modifications in lacunocanalicular morphology and network architecture can substantially impact the fluid dynamic microenvironment for mechanosensing osteocytes and, consequently, BMRs.