Metal-organic frameworks (MOFs) are of significant interest because of their high porosity, which facilitates their utilization in gas storage and catalysis. To enhance their current properties in these applications, it is necessary to elucidate the interactions between molecules in a confined environment that differ from those in bulk conditions. Herein, we study the confined molecular interaction by investigating the solvent-dependent photophysical properties of two different-sized molecules inside MOF-5. Ruthenium tris-bipyridine (Rubpy) and coumarin 153 (C153) are encapsulated in MOF-5. Rubpy with MOF-5 (Rubpy@MOF) is prepared by building MOF-5 around it, resulting in limited space for solvent molecules in the pores. The smaller C153 is encapsulated in the preformed MOF-5 (C153@MOF) by simply soaking the MOF in a concentrated C153 solution. C153@MOF permits more space for solvent molecules in the pore. Their characteristic absorption and emission spectra are examined to elucidate the confined molecular interactions. Rubpy@MOF and C153@MOF exhibit different spectral shifts compared to the guest molecules under bulk conditions. This discrepancy is attributed to the different micro-environments inside the pores, derived from confined host-guest interactions in the interplay of solvent molecules.