Background: In advanced cirrhotic conditions, hepatorenal syndrome detrimentally affects renal function. Interest has grown in propolis for its cytoprotective properties against various exogenous agents. This study evaluates the efficacy of Saudi propolis extracts in mitigating hepatorenal toxicity induced by carbon tetrachloride in mice. Methods: Thirty-two male Swiss Albino mice were divided into four groups: a Control (-) group receiving distilled water; a Control (+) group subjected to intraperitoneal CCl4 at 0.5 mL/kg (20% v/v in corn oil) on day 6; a Standard group treated daily with silymarin at 200 mg/kg and a group given an oral dose of aqueous propolis extract (APE) at 8.4 mg/kg. Result: Histological and biochemical analyses confirm propolis extract’s role in preventing hepatocyte apoptosis and reducing inflammatory infiltrates in kidney tissues, improving the histological appearance of hepatic and renal tissues with fewer fibrotic changes. The application of immunohistochemistry, along with reductions in anti-apoptotic proteins such as BCL-2 and p53, supports these findings, highlighting the antioxidant potential of Saudi propolis extracts in addressing hepatorenal toxicity.