The occurrence, frequency, and intensity of blade-strike of fish on an axial-flow marine hydrokinetic turbine was simulated using two modeling approaches: a novel scheme combining computational fluid dynamics (CFD) with Lagrangian particle tracking, and a conventional kinematic model. The kinematic model included simplifying assumptions of fish trajectories such as distribution and velocity. The proposed CFD and Lagrangian particle tracking methods provided a more realistic representation of blade-strike mechanisms by integrating the following components: (i) advanced unsteady turbulence simulation using detached eddy simulation (DES), (ii) generation of inflow turbulence based on field data, (iii) moving turbine blades in highly transient flows, and (iv) Lagrangian particles to mimic the potential fish pathways. The test conditions to evaluate the blade-strike probability and fish survival rate were: (i) the turbulence environment, (ii) the fish size, and (iii) the approaching flow velocity. The proposed Lagrangian method simulates potential fish trajectories and their interaction with the rotating turbine with the limitation that it does not include any volitional fish avoidance behavior. Depending upon the scenario, the percentage of particles that registered a collision event ranged from 6% to 19% of the released sample size. Next, by using a set of experimental correlations of the exposure-response for live fish colliding with moving blades, the simulated collision data were used as input variables to estimate the survival rate of fish passing through the operating turbine. The resulting survival rates were greater than 96% in all scenarios, which is comparable to or better than known survival rates for conventional hydropower turbines. The kinematic model predicted higher blade-strike probabilities and mortality rates than the Lagrangian particle-based method did. The Lagrangian method also offers the advantage of expanding the evaluation framework to include additional mechanisms of stress and injury on fish, or other aquatic biota, caused by hydrokinetic turbines and related devices.