The Loop Current mediating the oceanic heat and salt flux from the Caribbean Sea into the Atlantic Ocean and its interference with the Mississippi River discharge are critical for both the regional climate in the Gulf of Mexico area and the water vapor transport towards high northern latitudes. We present a 400-kyr record of sea surface temperature and local surface salinity from the northeastern Gulf of Mexico (IMAGES core MD02-2575) approximated from combined planktonic foraminiferal δ18O and Mg/Ca, which reflects the temporal dynamics of the Loop Current and its relationship to both varying Mississippi discharge and evolution of the Western Hemisphere Warm pool. The reconstructed sea surface temperature and salinity reveal glacial/interglacial amplitudes that are significantly larger than in the Western Hemisphere Warm pool. Sea surface freshening is observed during the extreme cool periods of Marine Isotope Stages 2, 8, and 10, caused by the strengthened Mississippi discharge which spread widely across the Gulf favored by the less established Loop Current. Interglacial and interstadial sea-surface conditions, instead, point to a strengthened, northward flowing Loop Current in line with the northward position of the Intertropical Convergence Zone, allowing northeastern Gulf of Mexico surface hydrographic conditions to approach those of the Caribbean. At these times, the Mississippi discharge was low and deflected westward, promoted by the extended Loop Current. Previously described deglacial megadischarge events further to the west did not affect the northeastern Gulf of Mexico hydrography, implying that meltwater routing from the Laurentide Ice Sheet via the Mississippi River is unlikely to have affected Atlantic Meridional Overturning Circulation.