The objective of the present study was to synthesize core-corona nanoparticles of doxorubicin (DOX) using hyaluronic acid-polyethyleneglycol-polycaprolactone (HA-PEG-PCL) copolymer for tumor targeting. Targeting efficiency of HA-PEG-PCL nanoparticles was compared with non-HA-containing nanoparticles (methoxy poly ethylene glycol (MPEG)-PCL). The copolymers were chemically synthesized and characterized by IR and NMR spectroscopies. The nanoparticles were characterized for shape and morphology by transmission electron microscopy, particle size, percentage of drug entrapment, and in vitro drug release profile. Differential scanning calorimetry and X-ray diffraction studies were also performed to appraise the crystalline or amorphous nature of DOX inside the polymer matrix. Formulations were prepared using different DOX:polymer ratios (1:1-1:3 w/w) and the optimum formulation with the drug:polymer ratio of 1:1 showed the mean particle size of 95 +/- 5 nm and entrapment efficiency of 95.56% in the case of HA-PEG-PCL nanoparticles, while the values were 115 nm and 95.50%, respectively, in the case of MPEG-PCL nanoparticles. The HA-PEG-PCL nanoparticles could release DOX for up to 17 days, whereas the MPEG-PCL nanoparticles could release it for up to 14 days. The hemolytic toxicity and hematological studies confirmed that both DOX-loaded HA-PEG-PCL and MPEG-PCL nanoparticles were safe and suitable for sustained and targeted drug delivery. The tissue distribution study and tumor growth inhibition were performed after intravenous injection of nanoparticles in Ehrlich ascites tumor (EAT)-bearing mice. The nanoparticles of HA-PEG-PCL copolymer accomplishes efficient delivery of DOX in EAT tumor when compared with the MPEG-PCL nanoparticles by the process of receptor-mediated endocytosis, as well as enhanced permeability and retention effect.