Hepatocellular carcinoma (HCC) dual targeted stimuli responsive nanoparticles (NPs) for intracellular delivery of doxorubicin (DOX) were developed based on a reduction cleavable hyaluronic acid–glycyrrhetinic acid conjugate (HA-Cyst-GA). HA-Cyst-GA conjugate readily formed NPs in aqueous milieu and exhibited a high drug loading capacity (33.9%). The NPs redox responsiveness evaluation showed a tendency to lose their structural integrity in response to a reductive stimulus while remaining stable at physiological conditions, and that drug release was dramatically accelerated in presence of an intracellular level of glutathione. Moreover, cellular uptake studies highlighted the affinity of hepatoma cells (HepG2) toward the NPs as compared to breast cancer cells (MDA-MB-231). HA-Cyst-GA DOX-NPs displayed an increased cytotoxic potency over their non-responsive counterparts and free DOX with IC50 of 5.75, 9.33 and 10.23 μg/mL, respectively. CLSM observations showed that HA-Cyst-GA DOX-NPs mediated a faster intracellular release and nuclear delivery of DOX as compared to the insensitive control. In vivo imaging study performed on H22 tumor bearing mice revealed a selective accumulation of DiR labeled NPs in the tumor and liver upon systemic administration. The antitumor efficacy was evaluated in HepG2 tumor xenograft model. Overall HA-Cyst-GA NPs appear as a potential HCC targeted intracellular delivery platform for DOX.