Three novel hybrid systems containing thioindigo (TI) as a guest molecule and MIL-68(In), MIL-68(Ga), and MOF-5 as host matrices were synthesized and studied with respect to their optical properties. Surprisingly, TI@metal–organic framework (MOF) systems do not exhibit photochromic response as a result of strong host–guest interactions, in which the E isomer is trapped in a parallel interaction motif between TI and the phenyl rings of the linker molecules. This binding site is assumed to be the origin of the occurring bright red solid-state fluorescence of TI inside the different MOF hosts. It was found that the corresponding decay times are significantly longer for TI@MOF than for pure TI. The emission wavelength of pure solid TI is also longer compared to its TI@MOF counterpart. These findings demonstrate that insertion into the MOF prevents aggregation between the TI molecules, which is beneficial to enhance the photoluminescence quantum yield. In addition to the experimental measurements, a series of density functional tight binding molecular dynamics (DFTB MD) simulations of E- and Z-thioindigo embedded in MOF-5 and MIL-68(Ga) have been performed, providing detailed insight into the host–guest interaction at the molecular level.