This work aimed to synthesize and characterize a nanocarrier that consisted of a ternary system, namely β-cyclodextrin-based nanosponge (NS) inclusion compounds (ICs) associated with silver nanoparticles (AgNPs) to increase the antimicrobial activity of quercetin (QRC). The nanosystem was developed to overcome the therapeutical limitations of QRC. The host–guest interaction between NSs and QRC was confirmed by field emission scanning electron microscopy (FE–SEM), X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), and proton nuclear magnetic resonance (1H–NMR). Moreover, the association of AgNPs with the NS–QRC was characterized using FE–SEM, energy-dispersive spectroscopy (EDS), transmission electron microscopy (TEM), dynamic light scattering (DLS), ζ-potential, and UV–Vis. Finally, the antimicrobial activity of the novel formulations was tested, which depicted that the complexation of QRC inside the supramolecular interstices of NSs increases the inhibitory effects againstEscherichia coliATCC25922, as compared to that observed in the free QRC. In addition, at the same concentrations used to generate an antibacterial effect, the NS–QRC system with AgNPs does not affect the metabolic activity of GES–1 cells. Therefore, these results suggest that the use of NSs associated with AgNPs resulted in an efficient strategy to improve the physicochemical features of QRC.