Nosocomial infections represent a major threat within healthcare systems worldwide, underscoring the critical need for materials with antimicrobial properties. This study presents the development of polyurethane foam embedded with silver nanoparticles (PUF/AgNPs) using a rapid, eco-friendly, in situ radiochemical synthesis method. The nanocomposites were characterized by UV–vis and FTIR spectroscopy, scanning electron microscopy coupled with energy dispersive X-ray technique (SEM/EDX), differential scanning calorimetry (DSC), dynamic mechanical analysis (DMA), tensile and compression strengths, antimicrobial activity, and foam toxicity tests. The resulting PUF/AgNPs demonstrated prolonged stability (over 12 months) and good dispersion of AgNPs. Also, the samples presented higher levels of hardness compared to samples without AgNPs (deformation of 1682 µm for V1 vs. 4307 µm for V0, under a 5 N force), tensile and compression strength of 1.80 MPa and 0.34 Mpa, respectively. Importantly, they exhibited potent antimicrobial activity against a broad range of bacteria (including Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Enterococcus faecalis) and a fungal mixture (no fungal growth on the sample surface was observed after 28 days of exposure). Furthermore, these materials were non-toxic to human keratinocytes, which kept their specific morphology after 24 h of incubation, highlighting their potential for safe use in biomedical applications. We envision promising applications for PUF/AgNPs in hospital bed mattresses and antimicrobial mats, offering a practical strategy to reduce nosocomial infections and enhance patient safety within healthcare facilities.