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The widespread use of antibiotics, corticosteroids, antitumor drugs, and immunosuppressive drugs increase the morbidity of invasive pulmonary aspergillosis (IPA). The ink secretion of molluscan species was identified as one of the novel sources of bioactive compounds. The present study demonstrated good in vitro and in vivo antifungal activity of Sepia ink extract (IE) against Aspergillus fumigatus. Compared with IPA group; IE treated, AMB treated, and AMB + IE-treated animals had a 67.80%, 83.41%, and 72.68% reduction in the pulmonary fungal burden, respectively. The recorded results of in vivo and in vitro studies demonstrate that IE has therapeutic effect against invasive pulmonary aspergillosis via reducing oxidative stress.