Background: Recently, silver nanoparticles (AgNPs) are involved in several biomedical, industrial and agriculture applications. However, the accumulation of these particles in the human body causes severe side effects on different vital organs. Phoenix dactylifera seed extract (PDSE) showed a biological activity as a hepatic-renal protective agent. Aim: This study was conducted to evaluate the hepatic-protective effect of the PDSE on AgNPs induced toxicity in mice. Materials and methods: Forty male mice were divided into 4 groups (n = 10) as follows: Gp1 was injected intraperitoneally (i.p) with 200µl sterile saline. Gp2 was injected i.p with PDSE (100 mg/kg) for a month. Gp3 was injected i.p with AgNPs (0.25 µl) for one month and Gp4 was injected with AgNPs as in Gp3 then injected with PDSE as in Gp2. Some hematological and biochemical parameters were determined with histological observation. Results: The results showed that injection of AgNPs led to toxicity in both liver and kidney organs as shown by elevation of liver enzymes aspartate transaminase, alanine transaminase, and kidney enzymes: urea and creatinine levels. Furthermore, the activity of antioxidant enzymes superoxide dismutase and catalase was decreased, while the level of malondialdehyde increased. Histologically, AgNPs injection altered the architectures of the liver and kidney tissues. Treatment with PDSE post-AgNPs injection ameliorated all previous parameters induced by AgNPs toxicity. Conclusion: PDSE has the potential to augment the pathophysiological alternation in the liver induced by AgNPs toxicity in mice.