Understanding lipase-mediated hydrolysis mechanisms within solid-state nanocarriers is fundamental for the rational design of lipid-based formulations. In this study, SBA-15 ordered mesoporous silica (MPS) particles were engineered with well-controlled nanostructural properties to systematically elucidate the role of intrawall microporosity, mesopore size, and particle structure on lipase activity. The microporosity and diffusional path length were shown to be key modulators for lipase-provoked hydrolysis of medium chain triglycerides confined within MPS, with small changes in the pore size, between 9 and 13 nm, showing now a clear correlation to lipase activity. Lipid speciation within MPS after lipolysis, obtained through H-1 NMR, indicated that free fatty acids preferentially adsorbed to rod-shaped MPS (RodMPS) particles with high microporosity. MPS that formed aggregated spindle-like structures (AggMPS) had intrinsically reduced microporosity, which was hypothesized to limit lipase/lipid diffusion to and from the MPS pores and thus retard lipolysis kinetics. A linear correlation between the microporosity and the extent of lipase-provoked hydrolysis was observed within both AggMPS and RodMPS, ultimately indicating that the intricate interplay between the microporosity and lipid/lipase diffusion can be harnessed to optimize lipolysis kinetics for silica-lipid hybrid carriers. The new insights derived in this study are integral to the future development of solid-state lipid-based nanocarriers that control the lipase activity for improving the absorption of poorly soluble bio-active compounds.