The present study introduces an overview of gentamicin-clay mineral systems for applications in biomedicine and then focuses on the development of a series of gentamicin/clay hybrid materials to be used as the bioactive phase of hydroxypropylmethylcellulose (HPMC) to produce bionanocomposite membranes possessing antimicrobial activity of interest in wound-dressing applications. Gentamicin (Gt) was adsorbed from aqueous solutions into a montmorillonite (Cloisite®-Na+) to produce intercalation compounds with tunable content of the antibiotic. The hybrids were characterized by CHN chemical analysis, energy-dispersive X-ray analysis, X-ray diffraction, Fourier-transform infrared spectroscopy, and thermogravimetric analysis, confirming the intercalation of Gt by an ion-exchange mechanism. The release of Gt from the hybrids was tested in water and in buffer solution to check their stability. Hybrids with various amounts of Gt were incorporated into a HPMC matrix at various loadings and processed as films by the casting method. The resulting Gt-clay/HPMC bionanocomposites were characterized by means of field-emission scanning electron microscopy, and were also evaluated for their water-adsorption and mechanical properties to confirm their suitability for wound-dressing applications. The antimicrobial activity of the bionanocomposite films was tested in vitro toward various microorganisms (Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecium, Acinetobacter baumannii, and Klebsiella pneumonia), showing a complete bacterial reduction even in films with small Gt contents.