Oceanographic dynamics in the Gulf of Tehuantepec (GT) are the direct consequence of climate variability, mainly influenced by the strong wind regime locally called “Tehuanos” and the interactions between the Intertropical Convergence Zone (ITCZ) and El Niño Southern Oscillation (ENSO). The area is characterized by intense upwelling driven by the Tehuanos within one of the largest Oxygen Minimum Zones (OMZ) in the world. Upwelling carries nutrient-rich subsurface waters to the surface and provides marine resources to the coasts conforming one of the main economic sectors in the region. In this study, sediment core MD02-2521 is used to perform the first high-resolution paleoceanographic reconstruction of the last 6 millennia in the GT. The main focus is put on the analysis of the benthic foraminifera (BF) assemblages inhabiting within the OMZ, which appear to respond to bottom oxygenation and climate variations of the last ~6000 years. The microfossil assemblages throughout the sediment core revealed, first, intervals where the lack of foraminifera provide evidence of episodes of strong deoxygenation that triggered the dissolution of calcareous foraminiferal tests, second, a long-term decline of bottom-water oxygenation in the last ~2500 years likely responding to the southward migration of the ITCZ. Last, variations in response to the transitions between cold and warm periods occurred during the last 2–2.5 millennia and cyclicities of 1470 years resembling Bond Cycles suggest a climatic connection between the Pacific and Atlantic Oceans during the late-Holocene.