This study demonstrates the potential use of Zr-based metal–organic frameworks as carriers of gradual-release chemotherapeutics for lung cancer therapy. The therapeutic efficacy of 5-fluorouracil (5-FU) was compared to that of -cyano-4-hydroxycinnamic acid (-CHC). The model group of UiO-66 varied the number of defects and the presence of additional amino groups, and their 5-FU and -CHC@UiO-66 composites were examined. Their performance in drug delivery was evaluated through dry powder inhalers. The drug release kinetics from prepared composites were studied in different media, including SBF and SLF fluids. The effects of the ionic environment, the presence of an amino group on the surface of the MOF structure, and the tendency of the introduced molecule to protonate were observed. The sorption mechanisms were corroborated with DFT modeling, showing the profound impact of the –NH2 groups on the adsorption energetics. For UiO-66, the mutual orientation of the aromatic rings in the molecule and the MOF linker indicate the presence of the - stacking. The accumulated covalent bond order between the adsorbate molecule and the MOF framework also supports the nature of the adsorption. The in vitro and in vivo studies emphasize both the safety and efficacy of the presented therapy.