The Seso Cave System (SCS, South Central Pyrenees, Northeastern Spain) develops in poorly soluble marly interstratum between limestone beds of Eocene age. We propose an innovative and singular pseudokarstic speleogenetic model under vadose conditions based on cave morphological evidence, physicochemical and mineralogical characteristics of the Eocene marly host rock, U–Th dating of cave deposits, and local geological and geomorphological information. Eocene marls are shown to be sensitive to dispersion processes supported by their high clay content and the high concentration of sodium and low electrical conductivity in the seepage water. Runoff inside the cave results from water that infiltrates through joints and seepage water in cave walls. Thereby piping processes become very active, triggering mechanical scouring and outwashing mechanisms. The hydraulic gradient required to develop piping activity is determined by regional fluvial incision. The base level controlling water discharge during opening of the SCS coincides with a terrace of the Ara River dated at 65 ka BP. Considering this age, as well as the U–Th age of the oldest speleothems dated in the cave at 38 ka BP, the timing of the SCS interstratal piping-cave speleogenesis is constrained to the Upper Pleistocene; very likely at the end of Marine Isotope Stage 4 during a period characterized by high water availability following glacial retreat in northern Iberian mountains.