The purpose of this study was the surface modification of nano MOF-5 (NMOF-5) or IRMOF-1 (Zn4O(C8H4O4)3) in order to prevent its rapid degradation in the phosphate-buffered saline (PBS), along with the simultaneous increase in its biocompatibility. The NMOF-5 sample was synthesized under the ultrasound irradiation and then it was loaded with acetaminophen and ibuprofen. Each assembly (NMOF-5@drug) was then coated with a silica layer. The obtained nanoparticles were identified by FT-IR spectroscopy, N2 adsorption porosimetry (BET), X-ray powder diffraction (XRD), the thermogravimetric analysis (TGA), and the field emission scanning electron microscopy (FE-SEM). UV/Vis spectroscopy was used to determine the release profile of the drugs from the bare and silica coated assemblies. Silica coating resulted in an enhanced stability in PBS, and the sustained release of each drug was achieved within 3 days. MTT (Methylthiazolyldiphenyl-tetrazolium bromide) assay on NIH3T3 mouse embryonic fibroblast cells as a model of the cell line showed that silica coating NMOF-5 with silica leads in the more biocompatibility and less cytotoxicity. The cell viability was increased up to 100% for the silica coated NMOF-5 compared to the bare NMOF-5. NMOF-5 and NMOF-5@silica were utilized in the injectable drug delivery for the first time. In this study, the toxicological studies about silica coated NMOF-5 in the drug delivery systems were developed.