One of the great challenges that face human is high mortality rate associated with invasive pulmonary aspergillosis (IPA). The sepia ink extract was studied for its potential antigenotoxic, antifungal and antioxidant effects against Aspergillus fumigatus in comparison to the common antifungal drug amphotericin B. Thirty-six mice were distributed randomly into four equal groups. All mice were immunosuppressed and infected with aspergillosis. Group I did not receive any treatment. The groups II, III and IV were treated after 1 day of infection with 200 mg ink extract, 150 mg amphotericin B and mixture of ink extract and amphotericin B, respectively. The current work showed that the ink extract has reduced the fungal load in the liver as well as the levels of fungal toxin gliotoxin in the serum. Throughout the 7 days’ post-infection, after treatment with ink extract and/or amphotericin B, glutathione (GSH) content and superoxide dismutase (SOD) activities in the serum were markedly increased whereas the levels of malondialdehyde (MDA) were significantly reduced. The tail length (TL), %DNA in tail, tail moment (TM) and olive tail moment (OTM) in the hepatocytes were significantly alleviated after treatment with ink extract and/or amphotericin B. We can conclude that although ink extract and amphotericin B separately showed their antifungal, antioxidant and antigenotoxic properties, the combination between them can lead tothe antagonistic effect.