The underground hydrogen storage (UHS) in depleted oil and gas reservoirs is widely acknowledged as the most promising method for large-scale hydrogen storage. The fluid-solid coupling effect during the long-term hydrogen storage plays a crucial role in influencing the long-term stability of the formation and assessing the efficacy of hydrogen storage. Utilizing nanoindentation techniques, this study investigates how variations in gas medium and water bearing characteristics affect the micromechanical properties of different rocks, subsequently evaluating optimal conditions for hydrogen storage. Continental shale exhibits superior hardness and a higher elastic modulus compared to greywacke and feldspathic sandstone. Fluid-solid coupling significantly enhances the structural stability of reservoir rocks; however, excessive reaction intensity may lead to increased hydrogen loss. Water, along with its H+ ions and weak acid anions, serves as an important reaction medium between hydrogen and rock materials, enhancing reaction intensity. Methane can adhere to mineral surfaces such as clay particles and pores, which reduces the amount of hydrogen available for interaction with inorganic minerals, further complicating these reactions. Taking into account fluid-solid coupling’s impact on formation stability and potential hydrogen loss during prolonged storage periods, depleted gas reservoir with low water saturation and methane as cushion gas may be an ideal large-scale underground hydrogen storage structure. These research findings are instrumental in identifying optimal conditions for hydrogen storage while providing valuable insights for site selection and development of depleted oil and gas reservoir-based hydrogen storage.