Background: Lead is an environmental pollutant has a negative effect on the immune system. Echinacea (E. purpurea) is an immunostimulant. Also, cerium oxide nanoparticles (CeONPs) are potential antioxidant elements. Objective: The current study was intended to assess the antioxidant and immunostimulant influences of CeONPs and Echinacea against lead induced immune toxicity. Methods: Forty nine male rats were allocated into 7 groups. Group1 served as the control group. Group2 rats were orally treated with lead acetate 60 mg/ kg b.wt/day. Group3 rats were intraperitoneally (i.p.) injected with CeONPs 0.5 mg/kg b.wt/day. Group4 rats were orally treated with E.P. 150 mg/ kg b.wt/day. Group5 rats were given lead as group2 in addition injected i.p with 0.5 mg/kg b.wt/day CeONPs. Group6 rats gained the above mentioned dose of lead plus 150 mg/kg b.wt E.P orally. Group7 rats were given Lead & Echinacea and CeONPs by doses as mentioned above, rats were treated for 2 weeks (5 days/week). Results: lead intake resulted in anemia with significant leukopenia and lymphopenia. Additionally, lead injected rats showed a significant increase in interleukin-6, and tumor necrosis factor-α (TNF-α). In contrast, sera-immunological parameters (interleukin-10, IgG, IgM) and testosterone levels were significantly reduced. Moreover, lead-induced spleen oxidative injury was detected by a significant increase in malondialdhyde level with notable reduction in reduced glutathione content and catalase activity. Treatment with Echinacea and CeONPs improved the hematological, immunological and histological alterations induced by lead. Conclusion: Echinacea. and CeONPs have antioxidant, anti-inflammatory and immunostimulatory effects and could ameliorate the lead-induced immunotoxicity and oxidative stress.