This study was conducted to evaluate the possible protective effects of the flavonoid-rich fraction of Aloe barbadensis leaf skin on cadmium (Cd)-induced toxicity in male albino rabbits. Cadmium is a notable environmental pollutant due to its wider range of toxic manifestations. The aqueous fraction of aloe extract (AAF) showed higher phenolics, flavonoids, and antioxidant capacity among other fractions, suggesting its rationale use in this study. Twenty-four rabbits were randomly divided into four groups, including the control group (receiving only vehicle), the Cd group (receiving Cd, 5.1 mg/kg/day), the AAF groups (receiving AAF, 200 mg/Kg/day), and the Cd+AAF group (receiving the same concentrations as the Cd and AAF groups). Oral treatment over a period of 40 days significantly increased (p<0.05) biochemical marker enzymes, including transaminases (AST, ALT), alkaline phosphatase, γ-glutamyl transferase, creatinine, and urea, while total bilirubin (Tb) and albumin were decreased on days 10, 20, 30, and 40 in the Cd group as compared to control. A significant decrease (p<0.05) in enzyme levels and increases in Tb and albumin for Cd+AAF were observed as compared to Cd-treated rabbits. Contents of superoxide dismutase, catalase, and vitamins C and E in liver and kidney tissues were significantly increased (p<0.05), while cadmium content was significantly decreased (p<0.05) for Cd+AAF rabbits as compared to Cd-intoxicated rabbits. Values of all the parameters in only the AAF group were near to control. The histopathological studies for liver and kidney have also supported the Cd+AAF group markedly reducing the toxicity of Cd in both tissues to near normal. Thus, the results suggest that the flavonoid-rich fraction of AAF may act as a natural protective agent against Cd toxicity via suppressing oxidative stress due to higher antioxidant activity.