The Middle–Late Jurassic opening of the central Atlantic and proto-Caribbean seaways connecting the Pacific with the Tethys Ocean combined with rising sea level led to a major oceanographic and climatic reorganization conducive to the development of widespread carbonate platforms and diverse reefs. The timing of this shift in carbonate production and opening of the Tethys Ocean is well-constrained from outcrops in Europe and western Asia and marked by a notable positive carbon isotope (δ13C) excursion in the middle Oxfordian Gregoryceras transversarium ammonite Zone, termed “MOxE”. However, the temporal constraints from the western arm of the circum-global seaway through the proto-Caribbean and Gulf of Mexico are not well resolved. Presented here are the first paired organic and carbonate carbon-oxygen isotope records from the Smackover Formation, Gulf of Mexico, that record a positive δ13C isotope excursion that is correlated to the middle Oxfordian transversarium Zone. These data are the first record of the MOxE in the Western Hemisphere and provide temporal constraints on the opening of the Gulf of Mexico. Furthermore, the existence of similar δ13C profiles from European basins strongly suggests a coeval response of the carbon cycle to the opening of the central Atlantic and proto-Caribbean seaways connecting the Pacific with the Tethys Ocean.