Most of the Ross Sea has been designated a marine protected area (MPA), proposed ‘to protect ecosystem structure and function’. To assess effectiveness, the Commission for the Conservation of Antarctic Marine Living Resources (CCAMLR) selected Adélie (Pygoscelis adeliae) and emperor (Aptenodytes forsteri) penguins, Weddell seals (Leptonychotes weddellii) and Antarctic toothfish (Dissostichus mawsoni) as ecosystem change ‘indicator species’. Stable for decades, penguin and seal populations increased during 1998–2018 to surpass historical levels, indicating that change in ecosystem structure and function is underway. We review historical impacts to population trends, decadal datasets of ocean climate and fishing pressure on toothfish. Statistical modelling for Adélie penguins and Weddell seals indicates that variability in climate factors and cumulative extraction of adult toothfish may explain these trends. These mesopredators, and adult toothfish, all prey heavily on Antarctic silverfish (Pleuragramma antarcticum). Toothfish removal may be altering intraguild predation dynamics, leading to competitive release of silverfish and contributing to penguin and seal population changes. Despite decades of ocean/weather change, increases in indicator species numbers around Ross Island only began once the toothfish fishery commenced. The rational-use, ecosystem-based viewpoint promoted by CCAMLR regarding toothfish management needs re-evaluation, including in the context of the Ross Sea Region MPA.