Introduction: Hepatocellular carcinoma is a major cause of morbidity and mortality worldwide. Sorafenib as a multi kinase inhibitor prolongs patients' survival for only a few months. Therefore, there is a great need for alternatives. It was proposed that itraconazole is a powerful inhibitor of angiogenesis and hedgehog signaling. Aim of the study: we aimed to examine the effect of itraconazole (300 mg/kg) administered orally as a monotherapy or as adjunct therapy with sorafenib (30mg/kg) on diethylnitrosamine-induced HCC in mice. Methods: Five micron serial sections from paraffin blocks were stained with hematoxylin and eosin. Slides were located in Mayer's Hematoxylin dye for three minutes followed by rinsing with distilled water. Then placed in Eosin dye for two minutes followed by rinsing with distilled water and three baths of alcohol with decreasing concentrations (80%-95%-100%) of three minutes each and two baths of xylene for another three minutes. Results: The administration of itraconazole demonstrated improved liver histology and demonstrated regression of tumor production rates that was linked to attenuation of fibrosis and inflammatory cell infiltration in addition to restoration of lobular architecture. Conclusion: These results suggest that itraconazole can serve as promising candidate in the management of HCC and further studies are warranted to investigate the underlying mechanisms behind its anti-tumor activity.