Persistent photoconductivity (PPC) is an intriguing physical phenomenon, where electric conduction is retained after the termination of electromagnetic radiation, which makes it appealing for applications in a wide range of optoelectronic devices. So far, PPC has been observed in bulk materials and thin-film structures, where the current flows in the plane, limiting the magnitude of the effect. Here using epitaxial Nb:SrTiO3/Sm0.1Bi0.9FeO3/Pt junctions with a current-perpendicular-to-plane geometry, a colossal X-ray-induced PPC (XPPC) is achieved with a magnitude of six orders. This PPC persists for days with negligible decay. Furthermore, the pristine insulating state could be fully recovered by thermal annealing for a few minutes. Based on the electric transport and microstructure analysis, this colossal XPPC effect is attributed to the X-ray-induced formation and ionization of oxygen vacancies, which drives nonvolatile modification of atomic configurations and results in the reduction of interfacial Schottky barriers. This mechanism differs from the conventional mechanism of photon-enhanced carrier density/mobility in the current-in-plane structures. With their persistent nature, such ferroelectric/semiconductor heterojunctions open a new route toward X-ray sensing and imaging applications.