CONTEXT: In the present study, hyaluronic acid (HA)-coated raloxifene-loaded poly(l-lactic-co-glycolic acid) (PLGA) nanoparticles have been developed to improve the anticancer potential and reduce side effects associated with the drug. AIM AND OBJECTIVES: The investigation was aimed to formulate and optimize raloxifene hydrochloride (RALH)-loaded PLGA nanoparticles with surface modification using HA as a targeting moiety. To perform physicochemical characterization, cytotoxicity study (using MCF-7), drug release study and pharmacodynamic study of optimized formulation. METHODOLOGY: Raloxifene hydrochloride-loaded PLGA nanoparticles were prepared by nanoprecipitation technique, followed by surface modification with HA. Formulation was optimized by using 23 factorial design and characterized by physicochemical, drug release, cytotoxicity studies, and pharmacokinetics. RESULTS AND DISCUSSION: The particle size, PDI, zeta potential, entrapment efficiency, and loading capacity of spherically shaped RALH-loaded nanoparticles were 207.3 ± 4.2 d.nm, 0.218 ± 0.127, -.127 mV, 43.75 ± 1.2%, and 7.55 ± 1.14%, respectively. The drug release showed sustained release and followed Korsmeyer-Peppas model with non-Fickian release pattern. The cytotoxicity study of drug-loaded NPs by MTT assay on MCF-7 breast carcinoma cell showed anti-cancer activity after 48 h of treatment. CONCLUSION: The results of the present investigation suggested that RALH-loaded HA-modified PLGA nanoparticles showed sustained drug release with anticancer activity and can be a promising approach for treatment of breast cancer.