<p>Green synthesis of multifunctional nanoconjugates has emerged as a promising strategy to enhance the therapeutic performance, biocompatibility, and physicochemical stability of conventional drugs. In the present study, a sustainable one-pot phytochemical-assisted approach was developed for the synthesis of metformin-conjugated zinc oxide nanoparticles (Met@ZnO NPs) using <i>Psidium guajava</i> leaf extract as a natural reducing, capping, and stabilizing agent. The synthesis parameters were systematically optimized to obtain stable, highly dispersed nanoconjugates with improved colloidal characteristics and enhanced therapeutic potential. The optimized Met@ZnO NPs exhibited excellent colloidal stability with a positive zeta potential of + 34.9 mV and a moderate polydispersity index (~ 0.2), indicating successful surface functionalization and stable dispersion. Comprehensive physicochemical characterization confirmed the successful formation of the hybrid nanosystem. UV–Vis spectroscopy revealed a bathochromic shift from 361 to 373&#xa0;nm with a corresponding reduction in band-gap energy, indicating effective electronic interaction between metformin and ZnO. FTIR and EDX analyses demonstrated successful metformin conjugation through Zn–N coordination and hydrogen-bonding interactions, while XRD confirmed preservation of the hexagonal wurtzite ZnO crystalline structure after functionalization. TEM analysis showed predominantly spherical nanoparticles with sizes ranging from 10 to 30&#xa0;nm, surrounded by a thin metformin-associated organic layer. Water contact angle studies revealed enhanced hydrophilicity following conjugation, whereas TGA demonstrated markedly improved thermal stability of the Met@ZnO nanoconjugates compared with pure metformin. The nanoconjugates also displayed improved saturation solubility in both phosphate-buffered saline and wound-simulating fluid, supporting enhanced aqueous dispersibility and bioavailability. Biological evaluation demonstrated significantly enhanced multifunctional therapeutic performance of Met@ZnO NPs compared with pristine ZnO NPs and free metformin. The nanoconjugates exhibited superior antidiabetic activity through potent α-amylase and α-glucosidase inhibition, alongside enhanced antioxidant activity in DPPH and ABTS radical scavenging assays. Furthermore, substantial anti-inflammatory activity was observed in protein denaturation models, highlighting the synergistic contribution of ZnO, metformin, and guava phytochemicals. The enhanced bioactivity was attributed to increased surface area, improved hydrophilicity, effective surface functionalization, and synergistic nano-bio interfacial interactions. Overall, this study demonstrates that <i>P. guajava</i>-mediated Met@ZnO nanoconjugates represent a promising eco-friendly and multifunctional therapeutic platform with improved solubility, stability, biocompatibility, and broad-spectrum biomedical potential for applications in diabetes management, oxidative stress-associated disorders, antimicrobial therapy, and wound-healing systems.</p> Graphical Abstract <p></p>