The Columbia River Basin faces a threat from the potential invasion of zebra mussels (Dreissena polymorpha), notorious for their ability to attach to various substrates, including concrete, which is common in fishway construction. Extensive mussel colonization within fishways may affect fish passage by altering flow patterns or creating physical barriers, leading to increased travel times, or potentially preventing passage altogether. Many factors affect mussel habitat suitability including vectors of dispersal, water parameters, and various hydrodynamic quantities, such as water depth, velocity, and turbulence. The objective of this study is to assess the potential for zebra mussels to attach to fishway surfaces and form colonies in the McNary Lock and Dam Oregon-shore fishway and evaluate the potential impact of this infestation on the fishway’s efficiency. A computational fluid dynamics (CFD) model of the McNary Oregon-shore fishway was developed using the open-source code OpenFOAM, with the two-phase solver interFoam. Mesh quality is critical to obtain a reliable solution, so the numerical mesh was refined near the free surface and all solid surfaces to properly capture the complex flow patterns and free surface location. The simulation results for the 6-year average flow rate showed good agreement with the measured water column depth over each weir. Regions susceptible to mussel infestation were identified, and an analysis was performed to determine the mussel’s preference to colonize as a function of the depth-averaged velocity, water depth, and wall shear stress. Habitat suitability criteria were applied to the output of the hydraulic variables from the CFD solution and provided insight into the potential impact on the fishway efficiency. Details on the mesh construction, model setup, and numerical results are presented and discussed.