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Antarctic ice sheet and climate evolution during the mid-Miocene has direct relevance for understanding ice sheet (in)stability and the long-term response to elevated atmospheric CO2in the future. Geologic records reconstruct major fluctuations in the volume and extent of marine and terrestrial ice during the mid-Miocene, revealing a dynamic Antarctic ice-sheet response to past climatic variations. We use an ensemble of climate – ice sheet – vegetation model simulations spanning a range of CO2concentrations, Transantarctic Mountain uplift scenarios, and glacial/interglacial climatic conditions to identify climate and ice-sheet conditions consistent with Antarctic mid-Miocene terrestrial and marine geological records. We explore climatic variability at both continental and regional scales, focusing specifically on Victoria Land and Wilkes Land Basin regions using a high-resolution nested climate model over these domains. We find that peak warmth during the Miocene Climate Optimum is characterized by a thick terrestrial ice sheet receded from the coastline under high CO2concentrations. During the Middle Miocene Climate Transition, CO2episodically dropped below a threshold value for marine-based ice expansion. Comparison of model results with geologic data support ongoing Transantarctic Mountain uplift throughout the mid-Miocene. Modeled ice sheet dynamics over the Wilkes Land Basin were highly sensitive to CO2concentrations. This work provides a continental-wide context for localized geologic paleoclimate and vegetation records, integrating multiple datasets to reconstruct snapshots of ice sheet and climatic conditions during a pivotal period in Earth’s history.