The incorporation of bioactive natural compounds into biomedical applications offers a promising route to enhance therapeutic efficacy while supporting sustainability. In this study, we investigated the synergistic potential of Sericin, a silk-derived biopolymer, and Chelidonium majus L. (C. majus), a medicinal plant with a diverse phenolic profile, in relation to biological activities relevant for wound care and infection control. A combined experimental strategy was applied, integrating detailed chemical characterization of C. majus extracts with antimicrobial and cytocompatibility assays across different Sericin–plant extract ratios (1:1, 1:2, 2:2, and 2:1). Phytochemical analysis identified and quantified 57 phenolic compounds, including high levels of flavonoids (quercetin, kaempferol, isorhamnetin) and phenolic acids (caffeic and ferulic acid). Salicylic acid (123.6 µg/g), feruloyltyramine (111.8 µg/g), and pinocembrin (98.4 µg/g) were particularly abundant, compounds previously reported to disrupt microbial membranes and impair bacterial viability. These metabolites correlated with the strong antimicrobial activity of C. majus against Gram-positive strains (MIC = 5–10 mg/mL). In combination with Sericin, antimicrobial performance was ratio-dependent, with higher proportions of C. majus (2:1) retaining partial inhibitory effects. Cytocompatibility assays with HFF1 fibroblasts demonstrated low antiproliferative activity across most formulations (GI₅₀ > 400 µg/mL), supporting their potential safety in topical applications. Collectively, the results indicate a concentration-dependent interaction between C. majus phenolics and the Sericin protein matrix, reinforcing their suitability as candidates for natural-based wound healing materials. Importantly, the valorization of Sericin, an underutilized byproduct of the silk industry, together with a widely accessible medicinal plant, underscores the ecological and economic sustainability of this approach. Overall, this work supports the exploration of the development of biomaterials with potential for advancing tissue repair and wound management.