Background <p>Liver cancer is one of the leading causes of cancer-related fatalities. This study investigates the role of lncRNA GABARAPL3/miR-155-5p/GABARAPL1 axis in modulating hepatic cancer progression.</p> Methods <p>The expression of GABARAPL1 and lncRNA GABARAPL3 expression in liver cancer tissues and cell lines using qRT-PCR or Western blot. Cell proliferation, cell cycle, apoptosis invasion and migration abilities of HepG2 and Hep3B cells were determined by CCK-8, flow cytometry, transwell and wound healing assays, respectively. A xenograft tumor model of nude mice was utilized to assess the GABARAPL3/miR-155-5p axis function in vivo.</p> Results <p>GABARAPL1 expression was downregulated in liver cancer, and GABARAPL1 overexpression suppressed proliferation, invasion, and migration of hepatic cancer cells. LncRNA GABARAPL3 was positively correlated with GABARAPL1 and downregulated in liver cancer. GABARAPL3 overexpression inhibited malignant behavior of cancer cells. Within cancer cells, the GABARAPL1 protein level was increased via GABARAPL3 overexpression and decreased through miR-155-5p overexpression, miR-155-5p overexpression attenuated the promotive effects of GABARAPL3 upon GABARAPL1. Moreover, the inhibitory effects of GABARAPL3 overexpression upon liver cancer aggressiveness were partially attenuated by miR-155-5p overexpression. In the xenograft tumor model, lncRNA GABARAPL3 overexpression suppressed tumor growth, increased GABARAPL1 protein levels, and decreased the levels of proliferative and metastatic markers. Conversely, miR-155-5p overexpression exerted oncogenic effects in vivo, and partially attenuated the anti-tumor effects of lncRNA GABARAPL3 overexpression.</p> Conclusion <p>The lncRNA GABARAPL3/miR-155-5p/GABARAPL1 axis modulates liver cancer cell proliferation, invasion, and migration. Restoring lncRNA GABARAPL3 expression to inhibit oncogenic miR-155-5p could account for a promising strategy in the treatment of liver cancer.</p>