Quercetin (QtN) displays low systemic bioavailability caused by poor water solubility and instability. Consequently, it exerts limited anticancer action in vivo. One solution to increase the anticancer efficacy of QtN is the use of appropriate functionalized nanocarriers that preferentially target and deliver the drug to the tumor location. Herein, a direct advanced method was designed to develop water-soluble hyaluronic acid (HA)-QtN-conjugated silver nanoparticles (AgNPs). HA-QtN reduced silver nitrate (AgNO3) while acting as a stabilizing agent to produce AgNPs. Further, HA-QtN#AgNPs served as an anchor for folate/folic acid (FA) conjugated with polyethylene glycol (PEG). The resulting PEG-FA-HA-QtN#AgNPs (further abbreviated as PF/HA-QtN#AgNPs) were characterized both in vitro and ex vivo. Physical characterizations included UV-visible (UV-Vis) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM), particle size (PS) and zeta potential (ZP) measurements, and biopharmaceutical evaluations. The biopharmaceutical evaluations included analyses of the cytotoxic effects on the HeLa and Caco-2 cancer cell lines using the MTT assay; cellular drug intake into cancer cells using flow cytometry and confocal microscopy; and blood compatibility using an automatic hematology analyzer, a diode array spectrophotometer, and an enzyme-linked immunosorbent assay (ELISA). The prepared hybrid delivery nanosystem was hemocompatible and more oncocytotoxic than the free, pure QtN. Therefore, PF/HA-QtN#AgNPs represent a smart nano-based drug delivery system (NDDS) and could be a promising oncotherapeutic option if the data are validated in vivo.