Injury and mortality of fish during downstream passage through hydropower turbines is among the leading direct impacts of hydropower. Understanding the relationships among various strike variables and injury and mortality rates are necessary for improvements in turbine design. We subjected three species of fish to simulated blade strike in laboratory studies with different blade thicknesses, impact velocities, and body orientations to develop relationships between these variables and probability of injury and mortality. Midbody strikes resulted in higher mortality than head strikes, and tail strikes produced the least mortality. Lateral strikes caused more mortality than dorsal and ventral strikes, and higher strike velocities and thinner blades contributed to increased mortality. Several injury types were significantly associated with increased mortality, including injuries to the operculum, gills, viscera, heart, liver, swim bladder, muscle, and bone fractures. Here, the results from this study will be used to define biologically based design criteria that can be used by turbine designers to improve designs (e.g., increased leading-edge thickness and slower turbine speeds) to minimize the probability and impact of blade strike.