Background: Lead is widely distributed in the environment and has been associated with a variety of negative health impacts. The present study investigated the use of Echinacea with lead acetate in decreasing or preventing the serious side effects of lead on the brains of male rats. Methods: Twenty-four rats were distributed into four groups randomly. Group1: Rats orally administered 1ml of distilled water followed by an intraperitoneal (I.P) injection of 1ml of physiological saline (control group). Group2: Rats I.P injected with lead acetate (50 mg/kg b.w/day, 3 days a week for 4 weeks). Group3: Rats orally administered Echinacea (150 mg/kg b.w./day for 4 weeks). Group4: Rats administrated with Echinacea plus lead acetate with the same doses of G2 and G3. Results: Lead exposure resulted in a significant elevation in nitric oxide (NO) production and malondialdehyde (MDA), along with a decline in reduced glutathione (GSH) and enzyme activities of superoxide dismutase (SOD) and catalase (CAT) in the rats' brain. These results were linked with significant increases in aminotransferase enzymes, lactate dehydrogenase (LDH), alkaline phosphatase (ALP) in brain tissues and serum thyroid stimulating hormone (TSH) levels. Abnormal histopathological changes and increased caspase-3 immunopositivity were also observed in comparison to control. The co-treatment with Echinacea in lead-exposed rats improved all of these changes. Conclusions: This study pointed out that Echinacea could be used as an alternative treatment to counteract the negative effects of lead acetate.