Herein, a multi-bioresponsive self-assembled nano-drug delivery system (HSSG) was constructed by conjugating the anticancer drug Geraniol (GER) to hyaluronic acid (HA) via a disulfide bond. The HSSG NPs displayed a uniform spherical shape with an average diameter of ∼110 nm, maintained high stability, and realized controlled drug release in the tumor microenvironment (pH/glutathione/hyaluronidase). Results of fluorescence microscopy and flow cytometry verified that HSSG NPs were selectively uptaken by human hepatocellular carcinoma cell lines HepG2 and Huh7 via CD44 receptor-mediated internalization. Studies on H22 tumor-bearing mice demonstrate that HSSG NPs could effectively accumulate at the tumor site for a long period. In vitro and in vivo studies show that HSSG NPs significantly promoted the death of cancer cells while reducing the toxicity as compared to GER. Therefore, the HSSG NPs have great potential in the treatment of tumors.