Chronic wounds often result in multiple infections with various kinds of bacteria and uncontrolled wound exudate, resulting in several healthcare issues. Advanced medicated nanofibres prepared by electrospinning have gained much attention for their topical application on infected chronic wounds. The objective of this work is to enhance the critical variables of ciprofloxacin-loaded polycaprolactone-silk sericin (PCL/SS-PVA-CIP) nanofibre production via the process of electrospinning. To examine the antibacterial effectiveness of PCL/SS-PVA-CIP nanocomposites, the material was tested against P. aeruginosa and S. aureus. The combination of PCL/SS-PVA-CIP exhibited potent inhibitory properties, with the most effective concentrations of ciprofloxacin (CIP) being 3 μg/g and 7.0 μg/g for each bacterium, respectively. The biocompatibility was evaluated by conducting cell reduction and proliferation studies using the human epidermal keratinocyte (HaCaT) cells and human gingival fibroblasts (HGFs) in vitro cell lines. The PCL/SS-PVA-CIP showed good cell compatibility with HaCaT and HGF cells, with effective proliferation even at antibiotic doses of up to 7.0 μg/g. The drug release effectiveness of the nanocomposites was assessed at various concentrations of CIP, resulting in a maximum cumulative release of 76.5% and 74.4% after 72 h for CIP concentrations of 3 μg/g and 7 μg/g, respectively. In summary, our study emphasizes the possibility of combining silk sericin (SS) and polycaprolactone (PCL) loading with CIP nanocomposite for wound management.