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Hyaluronic acid (HA) is widely adopted in tissue engineering and drug delivery. 5-(4-Hydroxyphenyl)-3H-1, 2-dithiol-3-thione (ADT-OH) is one of commonly used H2S donors. In our previous study, HA-ADT was designed and synthesized via coupling of HA and ADT-OH. In this study, compared with sodium hydrosulfide (NaHS, a fast H2S-releasing donor) and morpholin-4-ium (4-methoxyphenyl)-morpholin-4-ylsulfanylidenesulfido-\u03bb5-phosphane (GYY4137, a slow H2S-releasing donor), HA-ADT showed stronger inhibitory effect on the proliferation, migration, invasion, and cell cycle of human HCC cells. HA-ADT promoted apoptosis by suppressing the expressions of phospho (p)-protein kinase B (PKB\/AKT), p\u2010glycogen synthase kinase\u20103\u03b2 (GSK-3\u03b2), p\u2010\u03b2\u2010catenin, and also inhibited autophagy via the downregulation of the protein levels of p\u2010Smad2, p\u2010Smad3, and transforming growth factor\u2010\u03b2 (TGF\u2010\u03b2) in human HCC cells. Moreover, HA-ADT inhibited HCC xenograft tumor growth more effectively than both NaHS and GYY4137. Therefore, HA-ADT can suppress the growth of HCC cells by blocking the AKT\/GSK-3\u03b2\/\u03b2-catenin and TGF\u2010\u03b2\/Smad2\/3 signaling pathways. 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