Cisplatin (CP) is a powerful anticancer agent used in the treatment of a diverse type of cancers. Oxidative stress is one of the most important side effects limiting the use of cisplatin. The protective effects of methanolic extract (ME) and ephedrine (EP), major compound, of Ephedra alata on CP-induced damages were here assessed. Treatment with CP-induced nephrotoxicity and hepatotoxicity characterized by biochemical alterations. In fact, using CP reduced significantly glutathione (GSH) levels, enzymatic activities of superoxide dismutase (SOD), catalase (CAT), glutathione-S-transferase (GST), and increased malondialdehyde (MDA) content. Nonetheless, CP-treatment induced DNA damage at renal, hepatic, and blood cells and increased interferon gamma (IFNgamma) level in serum. Co-treatments of mice with ME normalized relative kidney/body weight, restored biochemical and oxidative stress parameters, reduced DNA damage and IFNgamma level. In conclusion, ME exhibited the best protective effect against CP damage compared with ephedrine. This is could be attributed to the presence of polysaccharides, organic acids, flavonoids, and tannins in addition to ephedrine alkaloids. These compounds were reported to play a major role in inhibiting and scavenging free radicals, providing an effective protection against CP- induced oxidative damage. Graphical abstract.