In this study, we describe the innovative use of metal–organic frameworks (MOFs) as propranolol (PRO) carriers for mephedrone (4-MMC) overdose treatment or supervised withdrawal. The group of model Zr-based MOFs including UiO-66, UiO-67, MOF-808, and NU-1000, and PRO@MOF composites were synthesised and characterised. The PRO release was tested in water and simulated body fluid (SBF) environments. The prepared PRO@MOF differed in the amount and pore sizes, as well as in the surface properties, which affected the kinetics of PRO release. The inhibitory effect of SBF resulted in a more gradual, and controlled PRO release from PRO@MOF composites, further confirming the feasibility of this type of solution in real applications. The sorption mechanism in prepared PRO@MOF composites was studied by molecular dynamics (MD) and density functional theory (DFT) calculations. The molecular calculations (ring orientation, partial charges and bond orders) confirmed π–π stacking as the main contribution to the interaction between the electronic structures of PRO molecule and MOFs linker. The in vivo studies demonstrated the lack of cytotoxicity of MOFs and composites, and pre-evidence confirmed the effectiveness of using PRO-loaded MOFs as drug carriers in a 4-MMC overdose. The study provides a new potential detoxification system for addicts.