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Lead is a heavy metal that produces toxicity in both humans and animals due to oxidative stress. The aim of this study was to synthesize through green channel and evaluate hepatoprotective effect of purslane seeds-selenium nanoparticles (PS-Se NPs) against lead acetate-induced liver toxicity. The PS-Se NPs were made and their particle size and zeta potential were measured. In addition, the IC50 of SP-Se NPs against the HepG-2 liver cancer cell line as well as and LD50 in rats were determined. The PS-Se NPs had a mean particle size of around 54.70 ± 4.55 nm, a negative zeta potential of +17.25 and the observed shape of the nanoparticle was spherical. Also, the IC50 of PS-Se NPs against HepG-2 liver carcinoma cell line is 92.66 μg/mL and the LD50 is 1695 mg/kg b.w. Daily oral administration of PS-Se NPs at concentrations of 33.9 and 84.75 mg/kg b.w. for 30 days to rats treated with lead acetate (0.6 mg/kg b.w.) resulted in significant improvements in ALT, AST, ALP, TNF-α, Bcl-2, P53 and MDA. In contrast, oral administration of PS-Se NPs increased the levels of SOD, GPx and GSH in the liver tissue of lead acetate-treated rats. Furthermore, PS-Se NPs almost normalized these effects in histoarchitecture and ultrasound scanning examination of liver tissue. The PS-Se NPs have protective activity against lead acetate-induced liver tissue injury in rats, according to the biochemical, histological and ultrasound scanning findings.