This work aimed to develop hyaluronic acid (HA) decorated pluronic 85 (P85) coated solid lipid nanoparticles (SLN) loaded with paclitaxel (HA-PTX-P85-SLN) and to evaluate its potential to overcome drug resistance and to increase antitumor efficacy in mice bearing cervical and breast tumor. P85-Distearoyl Phosphoethanolamine (DSPE) was synthesized from P85 and DSPE by coupling in the presence of 1,10-carbonyldiimidazole (CDI) as a catalyst. The SLN were prepared by the hot homogenization technique and electrostatic interaction. PTX-loaded SLN was characterized for mean diameter, zeta potential, morphology, entrapment efficiency (EE), drug loading capacity (LC) and in vitro drug release. In vivo animal evaluation containing antitumor effect, pharmacokinetics and biodistribution were conducted in mice bearing cervical and breast tumor. The HA-PTX-P85-SLN showed a mean diameter of 160.3nm, negative zeta potential (−31.6mV), EE of 88.2%, and LC of 4.9%. PTX from HA-PTX-P85-SLN exhibited greater sustained drug release profiles compared free PTX. Pharmacokinetics results indicated that HA-PTX-P85-SLN exhibited a 5.5-fold increase in AUC in comparison to free PTX. Biodistribution results revealed that HA-PTX-P85-SLN exhibited higher tumor drug concentration compared with free PTX.