The emergence of bacterial resistance has increased the economic burden of infectious diseases dramatically during the previous few decades. Multidrug resistance (MDR) is difficult to cure in both Gram-negative and positive bacteria and is often incurable with traditional and broad-range antibiotics. Therefore, developing techniques to increase the antibacterial activity of therapeutic drugs is essential. Metal-organic frameworks (MOFs) are extremely versatile hybrid materials made of metal ions coupled via organic bridging ligands. They have been widely used as an excellent vehicle for drug delivery due to their low toxicity, biodegradability, and structural stability upon loading and functionalization. The present study focused on the synthesis of mannose (MNS)-coated MOFs with enhanced surface contact with S. aureus cells. The MNS coating on the surface of MOFs enhances their adherence to bacteria by binding to lectins present on the bacterial cell, resulting in improved VCM cellular penetration and activity against resistant bacteria. Various techniques, including atomic force microscopy, DLS, TGA, FT-IR, and DSC, were employed to analyze MNS-coated MOFs. They were also evaluated for their efficacy against resistant S. aureus. The results indicated that when VCM was loaded into MNS-coated MOFs, their bactericidal activity rose dramatically, resulting in the greater suppression of resistant S. aureus. AFM investigation of S. aureus strains demonstrated total morphological distortion after treatment with MNS-coated drug-loaded MOFs. The results of this work suggest that MNS-coated MOFs may be effective for reversing bacterial resistance to VCM and open new pathways for improving antibiotic therapy for diseases associated with MDR.