Oxygen, carbon, and strontium isotope variations in vein-filling calcite and quartz cements and their host rocks are used to elucidate the origin, spatial and temporal evolution, and migration pathways of fluids in the detachment Nuncios fold complex, northeastern Mexico. The folded Mesozoic sedimentary sequence contains two regional paleohydrostratigraphic units separated by a unit of low permeability. Two main generations of cements are present in both paleohydrostratigraphic units. Distinct differences exist between δ18O, δ13C, 87Sr/86Sr, and fluid-inclusion temperatures of early vein-filling cements in the lower and the upper units. These differences, together with a strong correspondence between early cement and host-rock δ18O and δ13C values, suggest that early diagenetic fluids were compartmentalized between the two units. Late vein-filling cements have isotopic compositions and fluid-inclusion temperatures that converge to similar values, indicating a change to open fluid flow between the lower and upper units. We hypothesize that the fluid history of the Nuncios fold complex evolved in two main stages: (1) burial diagenesis and early folding, during which fluids were confined within individual units, and (2) late-stage folding, during which increased deformation associated with fold tightening caused the expulsion of fluid from the lower unit into the upper unit.