Lyosphere has been broadly used to deliver chemical and biotherapeutic entities. However, the fragile nature of lyospheres can result in challenges in operation, and there is no comprehensive understanding of its strength to resist directional stress. This research was aimed to develop an appropriate approach to comprehensively evaluate lyospheres' strength. An innovative method was developed to probe the shear strength of lyospheres employing a highly sensitive rheometer bundled with a bespoke 3D-printed holder. It is found that fracture energy could be considered as an appropriate descriptor for mechanical performance of lyospheres. At different RH, the strength of lyospheres was inversely proportional to the residual moisture content. Microstructure of lyospheres is found to be critical to explain the anisotropic mechanical properties. An aligned honeycomb-like structure was shown to directly correlate different fracturing-modes (buckling, collapsing and scissoring). The methods and results should provide insight for controlling lyospherical strength through formulation and processing. • An innovative mechanistic characterization was developed to study lyospheres. • Shear strength of fragile lyosphere is characterized for the first time. • The first report of humidity impact on mechanical properties of lyospheres. • Fracture-energy is identified as the best descriptor for the strength of lyospheres • An aligned honeycomb microstructure of lyospheres was revealed for the first time.