Background : Artemisia afra is a plant traditionally used for treatment of different diseases in many parts of the world including Ethiopia. Its effects on different organs, however, have not yet been investigated. The objective of the present study was, therefore, to evaluate the acute and sub-chronic toxic effects of aqueous leaf extracts of Artemisia afra on Liver, Kidney and some Blood parameters in Rats. Methods : For acute toxicity study, aqueous extracts of the leaves were administered in a single dose of 200, 700, 1200, 2200, 3200, 4200 and 5000mg/kg body weight, while the low dose (600mg/kg) and triple of lower dose (1800mg/kg) were used for sub-chronic toxicity studies. Selected hematological and biochemical parameters of the blood followed by histopathological analysis were... investigated after 90 days of daily administrations. The results were expressed as M ± SE, and differences at P < 0.05 were considered significant. Differences between the experimental and control groups were analyzed using one-way analysis of variance (ANOVA), followed by Dunnett’s T-test to determine their level of significance. Results : The current study showed that the median oral lethal dose (LD50) was greater than 5000mg/kg. Acute toxicity study revealed some changes in general behavior of the rats above 3200mg/kg. The levels of blood parameters did not change though AST level decreased significantly in female animals after 90 days of sub-chronic treatment with 1800mg/kg. Histopathological presentations were generally normal though there were mild mononuclear leukocytic infiltrations around the central venules & portal areas of rats’ liver at both 600 and 1800mg/kg dose. Furthermore, minor tubulointerstitial leukocytic infiltrations were observed in small areas of kidney sections treated at higher dose. Conclusion : The aqueous extract of Artemisia afra at the test doses did not show significant toxicity: the minor inflammatory changes observed in this study were not accompanied by significant change in any of the hematological and biochemical markers of liver injury. It might be a response to parenchymal cell death with causes ranging from infectious agents, exposure to toxicants, generation of toxic metabolites, and tissue anoxia.