During the mid-Pliocene warm period (mPWP; 3.264–3.025 Ma), atmospheric CO2 concentrations were approximately 400 ppm, and the Antarctic Ice Sheet was substantially reduced compared to today. Antarctica is surrounded by the Southern Ocean, which plays a crucial role in the global oceanic circulation and climate regulation. Using results from the Pliocene Model Intercomparison Project (PlioMIP2), we investigate Southern Ocean conditions during the mPWP with respect to the pre-industrial period. We find that the mean sea surface temperature (SST) warming in the Southern Ocean is 2.8 °C, while global mean SST warming is 2.4 °C. The enhanced warming is strongly tied to a dramatic decrease in sea ice cover over the mPWP Southern Ocean. We also see a freshening of the ocean (sub)surface, driven by an increase in precipitation over the Southern Ocean and Antarctica. The warmer and fresher surface leads to a highly stratified Southern Ocean that can be related to weakening of the deep abyssal overturning circulation. Sensitivity simulations show that the decrease in sea ice cover and enhanced warming is largely a consequence of the reduction in the Antarctic Ice Sheet. In addition, the mPWP geographic boundary conditions are responsible for approximately half of the increase in mPWP SST warming, sea ice loss, precipitation, and stratification increase over the Southern Ocean. From these results, we conclude that a strongly reduced Antarctic Ice Sheet during the mPWP has a substantial influence on the state of the Southern Ocean and exacerbates the changes that are induced by a higher CO2 concentration alone. This is relevant for the long-term future of the Southern Ocean, as we expect melting of the western Antarctic Ice Sheet in the future, an effect that is not currently taken into account in future projections by Coupled Model Intercomparison Project (CMIP) ensembles.