Linezolid (LNZ) is a new-generation synthetic molecule for the antibacterial treatment of severe infections, particularly in infective cases where the bacterial resistance to first-choice drugs is caused by Gram-positive pathogens. In this context, since 2009, some strains resistant to LNZ in patients with long-term treatments have been reported. Therefore, there is a need to use not only new drug molecules with antibacterial activities in the dosage form but also a different approach to pharmacotherapeutic strategies for skin infections, which lead to a reduction in the concentration of biocides. This work explores LNZ hosted at two isostructural MOFs, MOF-74(Zn) and MOF-74(Cu), as promising antimicrobial systems for gradual biocide release within 6 h. These systems reach a lower minimum inhibitory concentration (MIC) in comparison to free LNZ. Even a decreased MIC value is also observed, which is an encouraging result regarding the efficiency of the systems to control concentration-dependent antimicrobial resistance.