All of the drawbacks associated with the chemotherapy of cancer are the impetus for the search for newer and more efficacious drugs. Therefore, the current study aimed to evaluate the cytotoxic and antitumor efficacy of scyphozoan Rhizostoma octopus (rhizostome jellyfish) venom extract (RVE) against different tumor cell lines (in vitro) and Ehrlich ascites carcinoma (EAC)-bearing mice (in vivo), respectively. Four groups of female CD-1 mice (n=10) were allotted as follows: group-1 (Gp1) was served as control. Gp2-Gp4 were injected intraperitoneally (i.p) with 1×10⁶ EAC cells/mouse. After 24 hours, Gp3 and Gp4 were injected (i.p) with cisplatin (2 mg/kg) or with 1/10 LD₅₀ of RVE (180 mg/kg body weight, b.wt) daily for 6 consecutive days, respectively. On day 14, the b.wt change, tumor indices, hematological and biochemical parameters, as well as histological alterations of liver and kidneys tissues, were investigated. The results showed that RVE had high protein content with six bands ranging between 15-70 kDa, as measured by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The IC₅₀ of RVE against human hepatocellular (HepG-2) and breast cancer (MCF-7) cell lines were 808.4 and 896.4 µg/mL, respectively. In EAC-bearing mice, RVE treatment modulated the b.wt change, and decreased the tumor volume and the tumor cells count. In addition, the liver and kidney functions were improved in EAC-bearing mice treated with RVE, as evidenced by ameliorating their histological structure.