In setting fisheries management quotas, fish interactions with marine mammals are seldom considered. Even less often considered are indirect effects from fishing and species interactions or potential changes to ecosystem structure as marine mammal populations rebuild. To explore these interactions, we used a multi-species production model to evaluate the interactions between mixed fleet fisheries, their target species, and marine mammals, in an ecosystem representative of the Northeast USA continental shelf. We simulated changes to biomass and catch trajectories and compared these to the associated biological reference points for commercially important finfish and the current biomass levels of marine mammals. Marine mammal populations increased over time in our simulations (even with varying degrees of dependence on commercial species as prey) except when direct human-induced mortality was set much higher than observed. Greatly increased fishing mortality can reduce the rate of population increase for marine mammals, slowing recovery for some populations. This is due to the combination of reduced prey and increased interactions with fishing vessels (bycatch or vessel strikes) as fishing effort increases. Our model suggests that managing human-induced direct mortality of marine mammals is the most important factor for the recovery of their populations, but fishery management plays an important role in avoiding the additional stress of reduced prey populations. Marine mammal predation can also affect trajectories and reference points for commercially fished species. These types of evaluations of direct human-induced mortalities as well as trade-offs between mixed fishery fleets and protected species requirements are essential for the transition to ecosystem-based fisheries management.