Hepatocellular carcinoma (HCC) prognosis remains dismal due to postsurgical recurrence and distant metastasis. Therefore, novel prognostic biomarkers and therapeutic targets for HCC therapy are urgently needed to improve the survival of liver cancer patients. Our evidence suggests that SLC46A3 (the gene solute carrier family 46 (sodium phosphate), member 3) is a member of the SLC46 family and has a potential role in the progression and treatment of HCC. The objective of the present study was to estimate the expression pattern and biological function of SLC46A3 in the progression of HCC, which may serve as a promising biomarker for diagnosis and therapy. In order to determine the expression pattern of SLC46A3 in HCC, several public HCC databases and tissue chips were used to examine 129 sets of primary HCC and non-tumor adjacent tissues from patients who had undergone surgery. The expression of SLC46A3 in 80 sets of HCC and non-tumor adjacent tissues were then compared by RT-PCR and Western Blot. The proliferation, invasion, migration and sphere-forming abilities of SLC46A3 knock-down and overexpressing cell lines were evaluated and the expression of related molecules in the epithelial mesenchymal transition (EMT) were detected by RT-PCR, western blot and immunofluorescence assay. The IC₅₀ value was used to evaluate the effect of SLC46A3 on sorafenib resistance. A lung metastasis model of mice HCC was constructed to test the potential effect of SLC46A3 on cancer metastasis and a subcutaneous xenografted tumor mice model was designed to verify the effect of SLC46A3 on the resistance of HCC cell lines to sorafenib. The expression of SLC46A3 was down-regulated in 83.2% of human HCC tissues compared to non-tumor adjacent tissues. Tumors that expressed low levels of SLC46A3 had more aggressive phenotypes, and patients with these tumors had shorter survival times after surgery compared to patients whose tumors expressed high levels of SLC46A3. Hepatocellular carcinoma cell lines that stably overexpressed SLC46A3 inhibited the levels of migration and invasion compared with control HCC cells, and formed smaller xenograft tumors with more metastases in mice compared with HCC cells that did not overexpress SLC46A3. In addition, overexpression of SLC46A3 obviously inhibited epithelial-to-mesenchymal transition-activating transcription factors such as N-cadherin and Vimentin. Furthermore, descended of IC₅₀ showed that overexpressed SLC46A3 could reduce sorafenib resistance and improve drug response in vivo and in vitro. In conclusion, increased expression of SLC46A3 could favor a better clinical prognosis for patients with HCC, ameliorate sorafenib resistance, and improve drug response. SLC46A3 might serve as a potential prognostic biomarker and therapeutic target in HCC.