The global threat of multidrug-resistant infections requires new approaches for its management. A blend of polymethyl methacrylate (PMMA) and poly(ε-caprolactone) (PCL) electrospun nanofibrous membrane was utilised as a scaffold to sustain the release of three broad-spectrum antiseptics to combat multidrug-resistant (MDR) microorganisms. The scaffold was characterised by Fourier transform infrared spectroscopy, contact angle, and scanning electron microscopy. The latter revealed a random and smooth structure. The contact angle value of 81.8 ± 1.8 confirmed the hydrophilic nature of the scaffold, which is important for wound healing. The high surface-to-volume ratio of the scaffolds was utilised for loading benzoic acid (BA), methylparaben (MPB), and propylparaben (PPB) which were released during 72 h concentrations ranging between 0.20 and 0.8 mg mL⁻¹. The initial release of antiseptics was high and was then sustained for over 72 h. After 8 h, the burst release was 61.64 ± 4.11% for BA, 41.11 ± 2.98% for MPB and 34.32 ± 3.13% for PPB. The release profile of BA was superior to that of the MPB and PPB. The loaded scaffolds inhibited MDR-resistant methicillin-resistant Staphylococcus aureus, Escherichia coli and Candida albicans and were not cytotoxic to a fibroblast cell line. They inhibited their colonisation by the tested microorganisms to non-detectable counts or at least reduced microbial counts by at least 6–7 logs (p ≤ 0.001) for 72 h. Crystal violet techniques and electron microscopy confirmed colonisation inhibition. Because of their non-cytotoxicity and broad-spectrum antimicrobial activity, the antiseptic-loaded PMMA/PCL nanofibrous scaffolds could be utilised as wound dressings, particularly in non-healing wounds.