Leukemia is a typical blood cancer that is characterized by the numerous duplication and proliferation of white blood cells. The main aim of this study was to develop PTX-loaded multifunctional nanoparticles and target to leukemia cells. In this study, transferrin-decorated paclitaxel-loaded lipid nanoparticle (TPLN) was prepared with an aim to increase the chemotherapeutic efficacy in the leukemia cells. Results clearly showed the superior targeting potential of TPLN to the HL-60 cancer cells compared to that of the paclitaxel-loaded nanoparticles (PLN). To be specific, TPLN showed a significantly higher cytotoxic effect in the cancer cells compared to that of the PLN indicating the superior targeting efficiency of the Tf-decorated nanoparticle system. The IC50 value of TPLN was 0.45 μg/ml compared to 2.8 μg/ml for PLN. TPLN induced a most remarkable apoptosis of the cancer cells and much of the cells were distorted with huge presence of the apoptotic body formation. Importantly, TPLN showed a remarkable reduction in the viable cells proportion to ~ 65% with around ~ 30% apoptosis cells (early and late apoptosis). Overall, results clearly showed the targeting potential of ligand-conjugated lipid nanoparticle system to the leukemia cells that might pave the way for the successful cancer treatment.