The path to the discovery of anticancer drugs and investigating their potential activity has remained a quest for several decades. Suberoylanilide hydroxamic acid (SAHA), also known as "Vorinostat", is a well-known histone deacetylase inhibitor (HDACi) and has the potential to act as a therapeutic agent against tumorigenesis. Herein, we have fabricated SAHA incorporated into biocompatible and biodegradable poly(d,l-lactide--glycolide) PLGA nanoparticles (NPs) using a facile method of ultrasonic atomization and evaluated their anticancer property. We have explored their characteristics using dynamic light scattering (DLS), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HR-TEM), encapsulation efficiency, and drug release and have investigated their efficacy on U87 glioblastoma (GBM) cells. SAHA-PLGA NPs synthesized were of average mean size of 80 ± 23 and 105 ± 6.0 nm observed through cryo-field-emission gun SEM and HR-TEM with a polydispersity index of 0.068 and a ζ-potential value of -13.26 mV. The encapsulation efficiency was 53%, with a sustained release up to 48 h. The assessment of SAHA-PLGA NPs for their anticancer activity on U87 GBM cells showed cellular cytotoxicity with an IC of 19.91 μM. SAHA-PLGA NP-treated cells also showed suppression in migration with 8.77 μM concentration, and cell growth inhibition was observed in the wound scratch assay for up to 24 h. The cellular uptake studies have been utilized by time-dependent experiments, revealing their cellular internalization. Taking this into account, our present experimental findings indicate that SAHA-PLGA NPs could play a significant role in enhancing the effectiveness and bioavailability and reducing adverse effects of cancer chemotherapy. It also highlights the inherent potential of these biocompatible entities for chemotherapeutic applications in biomedical and pharmaceutics.