Hydrokinetic energy has been mainly studied in areas where the principal driver of the current is the tide. However, in certain areas river discharges play also a principal role. The exploitation of the hydrokinetic resource in such areas has its own peculiarities, dictated by the combined influence of the two driving agents. The objective of this paper is to investigate the exploitation of hydrokinetic energy in the Miño Estuary, the largest estuary in NW Spain and N Portugal, with a focus on the site-specific performance of hydrokinetic energy converters (HECs) and its intra-annual variability. A state-of-the-art hydrodynamics numerical model is implemented and successfully validated based on field data. A third-generation HEC—to be more specific, the new Smart Freestream Turbine (SFT)—is considered, and its performance at the location with the greatest potential is assessed by means of: (i) site-specific efficiency, (ii) availability factor, and (iii) capacity factor. We find that, whereas the site-specific efficiency does not vary significantly, the availability and capacity factors do experience substantial intra-annual (seasonal) variability. In summer and autumn, river discharges are low, and the tide dominates the hydrokinetic resource. In contrast, during winter and spring, the river discharges significantly contribute to the resource, leading to a considerable increase in the availability and capacity factors. More generally, the results imply that in areas subject to combined fluvial and tidal influences the performance of HECs may depart significantly from that in tide-dominated areas, and this departure must be carefully weighed in assessing a project.