In this paper, an extensive series of experiments was performed to investigate the evolution of poromechanical (dry, drained, undrained, and unjacketed moduli), transport (permeability), and strength properties during reservoir depletion and injection in a high-porosity sandstone (Castlegate). An overdetermined set of eight poroelastic moduli was measured as a function of confining pressure () and pore pressure (). The results showed larger effect on pore pressure at low Terzaghi’s effective stress (nonlinear trend) during depletion and injection. Moreover, the rock sample is stiffer during injection than depletion. At the same and , Biot’s coefficient and Skempton’s coefficient are larger in depletion than injection. Under deviatoric loading, absolute permeability decreased by 35% with increasing effective confining stress up to 20.68 MPa. Given these variations in rock properties, modeling of in-situ-stress changes using constant properties could attain erroneous predictions. Moreover, constant deviatoric stress-depletion/injection failure tests showed no changes or infinitesimal variations of strength properties with depletion and injection. It was found that failure of Castlegate sandstone is controlled by simple effective stress, as postulated by Terzaghi. Effective-stress coefficients at failure (effective-stress coefficient for strength) were found to be close to unity (actual numbers, however, were 1.03 for Samples CS-5 and CS-9 and 1.04 for Sample CS-10). Microstructural analysis of Castlegate sandstone using both scanning electron microscope (SEM) and optical microscope revealed that the changes in poroelastic and transport properties as well as the significant hysteresis between depletion and injection are attributed to the existence and distribution of compliant components such as pores, microcracks, and clay minerals.