Background <p>Sulfasalazine (SAS) has a certain inhibitory effect on cancer, but its therapeutic effect on intracranial metastasis of hepatocellular carcinoma (HCC) remains unclear.</p> Objective <p>The purpose of this study was to explore whether SAS has a beneficial effect on intracranial metastasis of HCC and reveal its potential molecular mechanism.</p> Methods <p>HCC cells were treated with SAS, and PIAS3/JAK1/STAT3 was regulated by siRNA, pcDNA 3.1 overexpression vector, and JAK inhibitors. The regulatory effects of SAS on the PIAS3/JAK1/STAT3 axis were evaluated by loss- and gain-of-function and rescue experiments. Cancer cells were evaluated by C11-BODIPY probe, MDA detection, iron ion detection, and LPO detection. Proliferation was assessed by clonal formation assay, apoptosis by flow cytometry, invasion and migration by Transwell assay, and EMT-associated protein expression by western blot. The ability of cancer cells to metastasize was evaluated by blood–brain barrier model and xenografted mouse model.</p> Results <p>SAS effectively hampered HCC cell proliferation, invasion, and migration and EMT process, induced apoptosis and ferroptosis of HCC cells, and prevented brain metastases (BMS) of HCC cells. SAS inhibited JAK1/STAT3 pathway activation in HCC cells by upregulating PIAS3. JAK1 inhibitor enhanced the impact of SAS on HCC, while PIAS3 had the opposite action.</p> Conclusion <p>SAS blocks JAK1/STAT3 pathway by upregulating PIAS3, thereby inducing ferroptosis and inhibiting BMS in HCC. Combined administration of SAS and JAK inhibitors may be a potential strategy for HCC with brain metastases.</p>