Although selenium nanoparticles (SeNPs) have attracted great attention due to their potential antioxidant activity and low toxicity, the application of SeNPs is still restricted by their poor stability. A combination of polysaccharides and SeNPs is an effective strategy to overcome the limitations. In this study, Polygonatum sibiricum polysaccharide (PSP) was used as a stabilizer to fabricate SeNPs under a simple redox system. Dynamic light scattering, transmission electron microscopy, energy dispersive X-ray, ultraviolet-visible spectroscopy, Fourier transform infrared, and X-ray photoelectron spectrometer were applied to characterize the synthesized PSP-SeNPs. The stability and the antioxidant activity of PSP-SeNPs were also investigated. The results revealed that the zero-valent and well-dispersed spherical PSP-SeNPs with an average size of 105 nm and a negative ζ-potential of −34.9 mV were successfully synthesized using 0.1 mg/mL PSP as a stabilizer. The prepared PSP-SeNPs were stable for 30 days at 4 °C. The decoration of the nanoparticle surface with PSP significantly improved the free radical scavenging ability of SeNPs. Compared to the H₂O₂-induced oxidative stress model group, the viability of PC-12 cells pretreated with 20 μg/mL PSP-SeNPs increased from 56% to 98%. Moreover, PSP-SeNPs exhibited a higher protective effect on the H₂O₂-induced oxidative damage on PC-12 cells and lower cytotoxicity than sodium selenite and SeNPs. In summary, these results suggest the great potential of PSP-SeNPs as a novel antioxidant agent in the food or nutraceuticals area.