Here, a series of S-scheme hybrid MIL-101(Fe)/WO3 samples were designed and prepared by tightly immobilizing MIL-101(Fe) nanoparticles on the surface of WO3 nanoplates via a simple solvothermal reaction. The in situ loading of MIL-101(Fe) promoted charge separation because of the successful construction of the S-scheme, significantly enhancing the photocatalytic activity to efficiently remove tetracycline hydrochloride (TCH). This smart structural design endowed the synthetic MIL-101(Fe)/WO3 hybrid sample with highly efficient visible light-driven photocatalytic activity and good photostability. The optimized MIL-101(Fe)/WO3(1:1) hybrid photocatalyst exhibited the highest photocatalytic efficiency with a photodegradation efficiency of up to 93.8%. Dissimilar to certain reports, the photocatalytic activity over hybrid MIL-101(Fe)/WO3 samples was majorly driven by photogenerated holes (h+). In addition, the S-scheme photocatalytic mechanism was fully demonstrated by systematic characterizations including active species capture experiments and electron paramagnetic resonance analyses. This study sheds light on the design and synthesis of S-scheme hybrid photocatalysts for highly efficient applications of photocatalysis for removing TCH.