Paracetamol (PCM)-induced toxicity is a well-established pharmacological model. Cotinus coggygria is a medicinal plant rich in polyphenols, including the flavonoid fustin. The aim of the present study was to evaluate the effects of the flavonoid fustin isolated from Cotinus coggygria heartwood in a model of PCM-induced liver damage. Male Wistar rats (n=48) were allocated to four groups: Control, PCM, F5+PCM, F10+PCM. The rodents were treated daily orally for nine consecutive days as follows: groups F5+PCM and F10+PCM – with fustin (suspended in a vehicle) at doses of 5 and 10 mg/kg, respectively; groups Control and PCM – with the vehicle. PCM was injected intraperitoneally (1.0 g/kg) on day 7. At the end of the experiment, serum and liver samples were prepared. PCM caused a severe liver damage confirmed by histopathological, immunohistochemical and biochemical indices. Compared to PCM group, in F5+PCM and F10+PCM groups, the hepatic necrosis, steatosis, ballooning degeneration, inflammation and expression of NF-κB were significantly reduced. Fustin treatment resulted in a significant reduction of serum activities of alanine aminotransferase and gamma-glutamyl transferase to levels that did not differ from the control values. The present study demonstrated a hepatoprotective effect of the flavonoid fustin in a rat model of acute paracetamol-induced toxicity.