Anthropogenic deoxygenation of the Baltic Sea caused major declines in demersal and benthic habitat quality with consequent impacts on biodiversity and ecosystem services. Using Baltic cod otolith chemical proxies of hypoxia, salinity, and fish metabolic status and growth, we tracked changes from baseline conditions in the late Neolithic (4500 BP) and early twentieth century to the present, in order to understand how recent, accelerating climate change has affected this key species. Otolith hypoxia proxies (Mn:Mg) increased with expanding anoxic water volumes, but decreased with increasing salinity indexed by otolith Sr:Ca. Metabolic status proxied by otolith Mg:Ca and reconstructed growth were positively related to dissolved oxygen percent saturation, with particularly severe declines since 2010. This long-term record of otolith indicators provides further evidence of a profound state change in oxygen for the worse, in one of the world’s largest inland seas. Spreading hypoxia due to climate warming will likely impair fish populations globally and evidence can be tracked with otolith chemical biomarkers.