Deep-sea carbonate deposition is a complex process that is encapsulated in the carbonate compensation depth (CCD)—a facies boundary separating calcareous sediments from non-carbonates. Knowing how the CCD has varied over time is important for understanding and predicting the distribution of seafloor sediments and assessing their role in the global carbon cycle. We focus on the South Atlantic Ocean where the most recent CCD curve is based on Deep Sea Drilling Project (DSDP) Leg 73 sites drilled in 1980 in the South Atlantic Ocean. We compute the South and central South Atlantic CCD from the Late Cretaceous to the present day using updated age models from 45 DSDP and Ocean Drilling Program sites and backtracking with lithology-specific decompaction, eustasy, and dynamic topography. Our models extend further back in time and show more fluctuations than previous reconstructions, with the CCD varying by hundreds of meters during a span of 2–3 m.y. The addition of eustasy and dynamic topography deepens the CCD by as much as 500 m between 74 Ma and 45 Ma, and by ∼200 m during the Cenozoic. The central South Atlantic CCD diverges from the average South Atlantic CCD during the Eocene and Miocene, when it was ∼1 km shallower. These regional deviations may be due to changes in primary productivity and/or carbonate dissolution leading to reduced carbonate accumulation rates. Our CCD curves highlight the importance of regional processes in carbonate deposition across the South Atlantic and provide improved constraints for the modeling of geochemical cycles.