Understanding how human impacts have interacted with natural variability to affect populations and ecosystems is required for sustainable management and conservation. The Baltic Sea is one of the few large marine ecosystems worldwide where the relative contribution of several key forcings to changes in fish populations can be analyzed with empirical data. In this study we investigate how climate variability and multiple human impacts (fishing, marine mammal hunting, eutrophication) have affected multi-decadal scale dynamics of cod in the Baltic Sea during the 20th century. We document significant climate-driven variations in cod recruitment production at multi-annual timescales, which had major impacts on population dynamics and the yields to commercial fisheries. We also quantify the roles of marine mammal predation, eutrophication, and exploitation on the development of the cod population using simulation analyses, and show how the intensity of these forcings differed over time. In the early decades of the 20th century, marine mammal predation and nutrient availability were the main limiting factors; exploitation of cod was still relatively low. During the 1940s and subsequent decades, exploitation increased and became a dominant forcing on the population. Eutrophication had a relatively minor positive influence on cod biomass until the 1980s. The largest increase in cod biomass occurred during the late 1970s, following a long period of hydrographically related above-average cod productivity coupled to a temporary reduction in fishing pressure. The Baltic cod example demonstrates how combinations of different forcings can have synergistic effects and consequently dramatic impacts on population dynamics. Our results highlight the potential and limitations of human manipulations to influence predator species and show that sustainable management can only be achieved by considering both anthropogenic and naturally varying processes in a common framework.