In this study, we developed novel hyaluronic acid cross-linked zein nanogels (HA-Zein NGs) to deliver the potential anticancer agent curcumin (CRC), a naturally occurring phytochemical drug in cancer cells. In vitro studies showed that they are highly compatible with the tested cell lines. They showed CD44 specific uptake in CT26 cell line more than by the CD44 receptor pre-inhibited CT26 cells. The CRC encapsulated HA-Zein NGs (HA-Zein-CRC NGs) found to exert a specific toxicity against CT26 sparing healthy normal fibroblast cells in vitro. The apoptotic effects were further confirmed with flow cytometry showing that the HA-Zein-CRC NGs exhibited high anticancer activity against the CT26 cells. The in vivo bio-distribution with a CT26 tumor model showed their high tumor accumulation thereby improved antitumor efficacy with a low dosage of CRC, compared to the previous reports. Thus, the preclinical studies clearly showed that these novel HA-Zein NGs would be highly beneficial in encapsulating hydrophobic drugs with improved pharmacokinetics thereby enhancing the therapeutic outcomes.