Intraosseous (IO) infusions are an emergency procedure for injection directly into the bone marrow when other routes of fluid resuscitation are impossible and the patient’s life or limb is at risk. Across the U.S., medical providers and state protocols recommend IO injections when intravenous (IV) access is unavailable. Despite its widespread use in some of the most acutely life-threatening conditions in the emergency room (ER), there is a lack of scientific studies supporting many IO protocols—like injection pressure—for which medical providers are legally obligated to abide by. In this paper, we mechanistically modeled a 15-gauge EZ-IO injection of saline into the proximal tibia of an average human adult to arrive at an evidence-based clinical recommendation for injection pressure. Our model solved the mass transfer equation for the transport of water and the Darcy equation together with the continuity equation for fluid flow in porous media. We modeled the proximal tibia as a 3D cylinder with a linearly varying diameter consisting of bone marrow concentric with a surrounding cortical bone layer. We assumed the tibia was thermally insulated from the rest of the circulatory system for the short time frame of the injection and the saline was pre-heated to body temperature prior to injection. We varied the input pressure for the infusion and reported its effect on both the infusion flow rate and the total volume of water delivered to the patient. Our simulations support the idea that IO injections offer a comparable alternative to IV injections in terms of both flow rate and total water uptake (i.e. patient rehydration). The simulation tracked the concentration of water associated with different injection pressures and found that increased pressure had diminishing returns on the infusion flow rate. From this novel finding, we recommend that IO device manufacturers prioritize using larger bore needle tips with lower inlet pressure to maximize flow rate while minimizing patient pain. Additionally, since our model found that the optimal pressure for a 15-gauge EZ-IO infusion was equivalent to current protocol recommendations (300 mmHg), future tests should model if IO infusion with other fluids and needle gauges produces different results. Moreover, the effectiveness of IO infusion in patients with “abnormal” bone conditions could also be modeled by changing the material properties of the tibia in the simulation, which could ultimately lead to different pressure recommendations depending on the patient’s anatomy and medical condition(s).