The current study aims to evaluate the hepatoprotective and antitumor efficacy of doxycycline, as an matrix metalloproteases-9 (MMP-9) inhibitor, in an in vivo model of hepatocellular carcinoma (HCC). HCC was induced experimentally by thiocetamide (200 mg/kg) in rats that were treated with doxycycline (5 mg/kg for 16 weeks). Tumor severity was evaluated by measuring α-fetoprotein (AFP) levels, histopathologically by investigating liver sections stained with hematoxylin/eosin and assessing the survival rate. Liver homogenates were used for the measurements of MMP-9, fascin and hepatic heparan sulfate proteoglycan (HSPG) levels. Oxidative stress markers [malonaldehyde (MDA) and glutathione] as well as fibroblast growth factor-2 (FGF-2) gene expression were also among the assessed indicators. HCC in human and animal samples showed significant elevation in the levels of MMP-9 (231.7, 90 %), fascin (33.17, 140 %), as well as FGF-2 gene expression (342 % in animal samples; all respectively), associated with a significant decrease in hepatic HSPG level. Treatment of rats with doxycycline increased the animal survival rate (90 %) and decreased serum AFP level. Moreover, doxycycline ameliorated fibrosis and the induced massive hepatic tissue breakdown. It also restored the integrity of hepatic HSPGs and showed a magnificent inhibitory effect of tumor invasion cascade by significantly reducing the activities of MMP-9 (42 %) and fascin (50 %), as well as reducing the gene expression of FGF-2 (85.7 %). Furthermore, the antioxidant impact of doxycycline was evidenced by the significant elevation in glutathione level and depressing MDA level. To this end, doxycycline, proved promising hepatoprotective and antitumor activity and opens, thereby, a new horizon against vascular migration ability of the tumor cells.