Graphene, a material with superior mechanical properties and nanometre thickness, has been proposed to encapsulate biological cells and maintain a native environment during imaging and probing. In addition to a more conventional approach that uses silicon nitride membrane, graphene encapsulation keeps the hydrated samples transparent to the incident electrons with desired charge reduction and minimal electron scattering. The characteristic of being impermeable to any gases and liquid allows the encapsulated samples to be investigated in a vacuum environment, a long standing hurdle for high resolution electron imaging. Monte Carlo (MC) simulation of the incident electrons is performed to investigate the mechanisms of how electron beam interacts with the target samples after the involvement of a graphene layer. Results suggest that graphene has minimal effects on the electron penetration during imaging. However, extra liquid between the cell and the graphene layer may significantly prevent the travel of secondary or backscattered electrons, and imaging parameters such as accelerating voltage should be tuned accordingly for the successful acquisition of hydrated cell images. Finite element analysis (FEA) is also performed to investigate the role of graphene in determining the actual stiffness of the encapsulated cells. The contact between graphene-wrapped cell and an Atomic Force Microscope (AFM) tip has been simulated, and the “composite” model has been recursively refined with the experimental results. It has been revealed that force-displacement curves are not significantly affected with the addition of a graphene layer, even considering the extremely high modulus of graphene. As a conclusion, a conventional AFM or other nanoindentation approaches will be able to probe live cells encapsulated by graphene, and mechanical properties measured will only require minor corrections.