Ovarian cancer (OvCa) is currently the fifth most lethal malignancy affecting women health owing to the lack of early diagnosis and treatment choices available before the disease has progressed to a later stage. Paclitaxel (PTX) has shown substantial antineoplastic action against a variety of human cancers, including OvCa, for multiple decades. Despite this, the therapeutic use of this drug is not yet adequate owing to surfactant-related toxicities and off-target effects. In response to these constraints, nanoparticle carriers have evolved as delivery tools for the biocompatible and target delivery of PTX. In this work, a novel polymeric PTX formulation was developed for targeted therapy of OvCa cells, which was achieved by prodrug engineering and HA decoration strategies. Further studies indicated that HA-coated nanodrugs (HA-PLA-PTX NPs) could preferentially accumulate in the CD44-expressing SKOV3 cells, which induced elevated cytotoxicity, reduced cell proliferation, and increased cell apoptosis. In vivo study also demonstrated that equivalent doses of HA-PLA-PTX NPs surpassed the clinical PTX formulation Taxol in a SKOV3 xenograft tumor model. In conclusion, HA-PLA-PTX NPs might be a potentially feasible delivery system for effective OvCa treatment.