Hippocratea africana (HA) extract has been widely reported for its anti-plasmodial and antioxidant activites. This study was designed to investigate the plants' ethanolic leaf extract on the liver and renal functions, and histology in experimental animal model. Fifteen female adult Wistar rats weighing 150-160 g were divided into 3 groups (A-C) of 5 rats each. Group A, the normal control received distilled water 4 ml/ kg body weight, groups B and C received HA extract (524.4 and 786.6 mg/kg body weights respectively); representing 20% and 30% of LD 50 which was 2622.2 mg/kg body weight. Extract administration was by orogavage for 28 days, and serum was collected for renal and kidney function tests using standard procedures. Liver and kidney were excised, fixed in 10% formal saline, processed and stained with H&E, and Masson's trichrome stains for light microscopy. Signs of behavioural toxicity or mortality were not observed during the experiment, however, mild to moderate morphological alterations were demonstrated in both the liver and kidney of test animals with the widening of the urinary space, atrophy of the glomerulus, foci hyperplasia, and tubular swelling of the kidney in groups B and C animals, and this was corroborated in the liver, where there was mild to moderate widening of sinusoidal spaces with some presence of fatty changes. The liver function test indicated increasing serum enzymes of which alkaline phosphatase was significantly (p < 0.05) increased in groups B and C, whereas renal function test were significantly (p < 0.05) increased in these groups particularly of serum creatinine and urea. In conclusion, increasing doses and duration of HA administration may lead to severe hepato-renal complications.