<title>Abstract</title> Objective This study evaluated the combined therapeutic effects of cisplatin-loaded PEG-PLGA nanoparticles (CIS-PEG-PLGA) and nimotuzumab (NIMO) on glioblastoma (GBM) cells, focusing on their antiproliferative, apoptotic, and cell cycle-modulatory effects. Materials and Methods PEG-PLGA nanoparticles were synthesized using a double-emulsion solvent evaporation method, achieving a mean particle size of ~ 450 nm. Cisplatin release kinetics, proliferation, apoptosis, and cell cycle progression were assessed in U87 glioblastoma cells. The treatments included free cisplatin (CIS), CIS-PEG-PLGA, NIMO, and their combinations. Experiments were performed in triplicate, and statistical analyses included ANOVA test. Results The CIS-PEG-PLGA nanoparticles exhibited sustained cisplatin release, with 50% released within 8 h and nearly 100% within 72 h. The combination of CIS-PEG-PLGA + NIMO reduced cell proliferation by 90%, significantly surpassing that of CIS (50%) and CIS-PEG-PLGA (70%). Apoptosis rates were highest in the combination group (27.52%), followed by CIS (18.59%) and CIS-PEG-PLGA (25.95%). Cell cycle analysis revealed significant G2 phase arrest (30.12%) in the combination treatment group, highlighting its superior modulatory effects on cell cycle progression. Conclusion The combination of CIS-PEG-PLGA and NIMO demonstrated synergistic therapeutic effects in glioblastoma cells, enhancing antiproliferative, apoptotic, and cell cycle-modulatory outcomes. This approach represents a promising advancement in glioblastoma therapy by integrating nanotechnology and immunotherapy to overcome conventional treatment limitations. Further, in vivo studies are warranted to validate these findings and explore their clinical applications.