Melanoma excision procedures frequently result in complex wounds that require simultaneous tumor suppression and tissue regeneration. However, current post-surgical care heavily relies on synthetic drugs, facing challenges like antibiotic resistance and delayed healing. To address this notable gap, this study introduces a novel “mineral-botanical” hybrid nanofibrous dressing to reduce reliance on conventional synthetic agents. The nanofiber surfaces were subsequently functionalized with a supercritical CO₂ extract of Inula helenium, thereby introducing a highly bioactive botanical agent not previously explored in this hybrid wound-care context. Comprehensive physical and structural characterizations demonstrated that the bioactive coating serves as a resilient physical barrier, significantly enhancing the dressing’s structural integrity in fluidic environments. In vitro biological evaluations revealed a dual-action mechanism: the biomaterial exhibited excellent biocompatibility and accelerated migration in human dermal fibroblasts (HDFs), achieving nearly 100% in vitro wound closure at 24 h. Conversely, the Inula helenium-coated nanofibers demonstrated distinct, selective cytotoxicity against A375 melanoma cells, effectively restricting their proliferation and reducing their viability. Furthermore, the hybrid platform exhibited significant antioxidant potential and achieved 94% antibacterial inhibition against Staphylococcus aureus. In conclusion, this study presents a sustainable, dual-function wound dressing that suppresses residual cancer cells while promoting healthy tissue regeneration, offering a promising alternative to conventional synthetic oncological dressings.