Cerium oxide nanoparticles (CeO2 NPs) are being widely explored as therapeutic agents against neurodegenerative diseases due to their regenerative and strong antioxidant activity. The current study aims to investigate the protective effect of green synthesized CeO2 NPs using Aspergillus terreus (A. terreus) filtrate against rotenone-induced cytotoxicity in SH-SY5Y cells as an in-vitro Parkinson’s model. The CeO2 NPs were characterized using powder X-ray diffraction (PXRD), Fourier transform infrared (FTIR) spectroscopy, UV–visible (UV–vis) spectroscopy, Scanning electron microscopy (SEM), and High-resolution transmission electron microscopy (HR-TEM). PXRD data revealed the strain and the crystal grain size of the CeO2 NPs were 3.488 x 10-4 and ∼ 15 nm respectively. FTIR spectra exhibited the metal–oxygen bond (Ce–O) at 848 and 558 cm−1. The absorption peak at 352 nm obtained through UV–vis spectroscopy is because of the charge transfer from the valance band to the conduction band. SEM and HR-TEM analysis disclosed the formation of spherical-shaped CeO2 NPs within the size range of 8–12 nm. Our results revealed that CeO2 NPs dose-dependently attenuated the rotenone toxicity and reduced LDH release. Additionally, the flow cytometric studies revealed the concentration-dependent cellular uptake of CeO2 NPs. Further, the CeO2 NPs significantly attenuated the rotenone toxicity by suppressing ROS generation, and modulating apoptosis. Hence, our study suggests that the CeO2 NPs hold promising potential as nanotherapeutics against Parkinson’s disease.