Structural changes of the flexible metal–organic framework [Cu(Me-4py-trz-ia)] (1), which shows exceptionally high adsorption capacities for H2 and CO2, were characterized in detail by X-ray powder diffraction and single crystal structure analysis accompanied by DFT modelling after different solvent exchange procedures and at different stages of the activation process. Removal of solvent molecules from the pores within minutes results in a partially activated material that exhibits contracted pores due to hydrogen bonds between rearranged coordinating water molecules and the MOF framework. Further activation causes a release of all coordinating water molecules and, consequently, a re-opening of the pores to achieve the fully desolvated MOF with a similar unit cell as the non-activated, as-synthesized material. If all water molecules in the framework are replaced by methanol prior to activation, the pore contraction and re-expansion can be avoided, which allows not only a faster activation of the material at lower temperatures but also avoids fragmentation of the crystals of the empty framework. DFT calculations confirm the different activation routes, depending on solvent exchange procedures and kinetics of the water removal. Computed binding energies for H2 adsorption in the fully activated framework are nearly independent of H2 loading and adsorption position. Inelastic neutron scattering (INS) experiments at different H2 loadings suggest simultaneous multiple adsorption sites occupancy at low loading levels which is in good agreement with the computational results. Most sensitive to the pore filling by hydrogen, at the microscopic level, appeared to be the rotational dynamics of the methyl group, as an intrinsic interactions probe.