Metal-organic frameworks (MOFs) have received significant interest as a promising photocatalyst for environmental remediation due to its high surface area and porous nature. The small pores (<2 nm) in microporous MOFs help the adsorption of small molecules but limits diffusion and accessing of bigger molecules from MOF cavities, thus preventing their applications in some situation. The aim of this work is to fabricate mesoporous MOF composite with larger pore sizes (>2 nm) and open pore cavities that can provide right pathways for ingoing and outgoing of molecules during catalysis. Herein, we successfully report stable mesoporous MIL-100(Fe) loaded with ZnO NS by an in situ self-assembly method. The prepared samples were characterized by Brunauer-Emmett-Teller (BET) and N-2 adsorption-desorption isotherm to study their surface area and porosity. The catalytic performance of mesoporous MIL-100(Fe) was approximately 2-3 order of magnitude more than that of microporous MIL-100(Fe). Such higher catalytic activity in mesoporous MIL-100(Fe) can be ascribed to its mesocellular structure which can improve the molecular diffusion and accessibility inside MOF channels. The charge separation efficiency and photo-Fenton activity of mesoporous MIL-100(Fe) can further be increased by introduction of certain amount of ZnO NS and H2O2. Moreover, the as synthesized sample shows higher photo Fenton degradation efficiency at lower pH value with certain amount of H2O2. Lastly, the possible catalytic mechanism has been tentatively proposed. This study not only used for the pollutants degradation but also provide useful platform for the application of mesoporous MOFs as an efficient photo-Fenton activity to various other fields.