The current study evaluated the protective effect of Costus root extract against the hematology, biochemistry, histopathology and ultra-structure changes induced in rat liver due to the sub chronic exposure with melamine. In recent years manufacturers adding melamine (MA) to milk to increase its protein content but this led to toxic effects on many organs such as kidneys, liver, brain, etc. in experimental animals. Recent studies have proved that Costus root extract has a hepatoprotective role and has many health-related benefits showed against various toxins related to oxidative stress. Eighty adult albino rats (200–250 gm) were further allocated into 04 equal sets; set 01 exposed with distilled water orally, set 02 exposed with costus plant extract (0.4 mg/ kg) orally, set 03 exposed with MA (50mg/kg b.wt/day), and set 04 exposed with MA (50 mg/kg b.wt/day) plus costus plant extract (0.4 mg/ kg) orally for the period of two months. The experimental rats were exposed to general anesthesia before the sacrifice and the sample of blood and liver were collected. The samples were further prepared for histopathological and ultrastructural examinations. The results revealed that MA treatment (set 03) caused hematological, biochemical, histopathological, and ultrastructural alterations. Co-administration of Costus root extract with MA ameliorated most of the toxic effects of melamine (set 04). The results demonstrated that Costus root extract exhibited a protective effect by decreasing the toxic pathological changes caused by MA in the liver of albino rats.