Localized cancer rates are on an upsurge, severely affecting mankind across the globe. Timely diagnosis and adopting appropriate treatment strategies could improve the quality of life significantly reducing the mortality and morbidity rates. Recently, nanotherapeutics has precipitously shown increased efficacy for controlling abnormal tissue growth in certain sites in the body, among which ligand functionalized nanoparticles (NP) have caught much attention for improved survival statistics via active targeting. Our focus was to repurpose the antihelminthic drug, niclosamide (NIC), which could aid in inhibiting the abnormal growth of cells restricted to a specific region. The work here presents a one-pot synthesis of niclosamide encapsulated, hyaluronic acid functionalized core-shell nanocarriers [(NIC-PLGA NP)HA] for active targeting of localized cancer. The synthesized nanocarriers were found to possess spherical morphology with mean size of 150.8 ± 9 nm and zeta potential of -24.9 ± 7.21 mV. The encapsulation efficiency was found to be 79.19 ± 0.16% with a loading efficiency of 7.19 ± 0.01%. The nanohybrids exhibited extreme cytocompatibility upon testing with MDA-MB-231 and L929 cell lines. The rate of cancer cell elimination was approximately 85% with targeted cell imaging results being highly convincing. [(NIC-PLGA NP)HA] demonstrates increased cellular uptake leading to a hike in reactive oxygen species (ROS) generation, combating tumour cells aiding in the localized treatment of cancer and associated therapy.