We investigated the primary drivers of changes in the partial pressure of carbon dioxide (pCO2) together with the seasonal and interannual variability in the water-air net carbon dioxide flux (FCO2) in the lower estuarine zone surface waters of Patos Lagoon, the largest choked lagoon worldwide. Sampling occurred monthly during May 2017-June 2021 at the estuary’s inner inlet and mouth, which are contrasting hydrodynamic zones in the Patos Lagoon Estuary (PLE). The water pCO2 was mainly controlled by seasonal changes in total alkalinity and total dissolved inorganic carbon. The lower zone experienced periods of CO2 ingassing (austral summer/autumn) and CO2 outgassing (austral winter/spring). During summer/autumn, both protected and sea-exposed areas uptake an average of –15 mmol m−2 d−1 CO2, whereas during winter/spring, CO2 emissions prevail, reaching an average of 22 mmol m−2 d−1 at the inner estuary. Additionally, while much of the CO2 absorbed in summer/autumn is released to the atmosphere in the inner estuarine zone, the summer/autumn CO2 uptake in the estuary mouth is 4-fold higher than the winter/spring CO2 released. Unlike most estuarine systems, the PLE acted as a net CO2 sink of –2 mmol m−2 d−1 during the period investigated. The balance between CO2 uptake and emissions in the PLE was modulated by the combination of wind speed, freshwater discharge, water temperature, and outflow/inflow currents. Furthermore, phytoplankton blooms and strong wind-induced vertical mixing lead to highly variable CO2 exchanges. The highest estuarine CO2 concentration by autochthonous production indicates heterotrophy in estuarine waters. Part of this carbon produced in the estuary is exported to the coast, as evidenced by the high CO2 concentration in the estuary mouth. Therefore, the lower estuarine zone resists increased CO2 concentrations and has overcome regional anthropogenic emissions. The regional FCO2 range and complex PLE biogeochemistry dynamics need ongoing investigation to improve knowledge of regional CO2 exchanges and elucidate the role of large estuaries and coastal bays in the global carbon budget.