Though crucial for natural bone healing, local calcium ion (Ca²⁺) and phosphate ion (P_i) concentrations can exceed the cytotoxic limit leading to mitochondrial overload, oxidative stress, and cell death. For bone tissue engineering applications, H₂S can be employed as a cytoprotective molecule to enhance mesenchymal stem cell (MSC) tolerance to cytotoxic Ca²⁺/P_i concentrations. Varied concentrations of sodium hydrogen sulfide (NaSH), a fast-releasing H₂S donor, were applied to assess the influence of H₂S on MSC proliferation. The results suggested a toxicity limit of 4 mM for NaSH and that 1 mM of NaSH could improve cell proliferation and differentiation in the presence of cytotoxic levels of Ca²⁺ (32 mM) and/or P_i (16 mM). To controllably deliver H₂S over time, a novel donor molecule (thioglutamic acid—GluSH) was synthesized and evaluated for its H₂S release profile. Excitingly, GluSH successfully maintained cytoprotective level of H₂S over 7 days. Furthermore, MSCs exposed to cytotoxic Ca²⁺/P_i concentrations in the presence of GluSH were able to thrive and differentiate into osteoblasts. These findings suggest that the incorporation of a sustained H₂S donor such as GluSH into CaP-based bone graft substitutes can facilitate considerable cytoprotection, making it an attractive option for complex bone regenerative engineering applications.