Flexible metal-organic framework (MOF) materials have the ability to perform stimulated sudden volume contractions, and thus attract increasing attention for use in potential applications such as: actuators or sensors. Here, the structural transition of MIL-53(Cr) loaded with a high concentration of CH3OH (CH3OH) guest molecules, which cause internal pressure due to guest-guest interactions, was investigated. The pressure triggering the structural transition can be enhanced by high guest molecule loadings (1 CH3OH per unit cell (UC): 5 MPa, empty: 53 MPa, 7 CH3OH per UC: 90 MPa, and 8 CH3OH per UC: 280 MPa). The asymmetrical and small distortion of the organic-inorganic connections are the main microscopic characteristic of the structural transition of MIL-53(Cr) with a high CH3OH loading. The external pressure and the internal pressure, instead of the adsorption of the guest molecules, became dominant in the structural transition of MIL-53(Cr). Current studies showed that the high-pressure response of the flexible MOF structure may broaden the acceptable pressure range in future actuator or sensor applications.