Signal transducer and activator of transcription 3 (STAT3) is involved in the survival, proliferation, angiogenesis, invasion and metastasis of tumor cells. In addition, interleukin-6 (IL-6) has been reported to be closely related to STAT3 activity. In the present study, we investigated whether crocin, a major glycosylated carotenoid derived from saffron, can modulate the IL-6/STAT3 pathway to induce growth inhibition and sensitivity to cancer cell apoptosis. We determined that crocin inhibited STAT3 activation induced by IL-6 in hepatocellular carcinoma Hep3B and HepG2 cells. STAT3 suppression was mediated through the inactivation of Janus kinase 1/2(JAK1, JAK2) and Src kinase in both liver cancer cell lines. Furthermore, crocin induced the expression of protein tyrosine phosphatase (PTP) SHP-1, which led to STAT3 dephosphorylation. Deletion of the SHP-1 gene by siRNA recovered the inhibitory effects of crocin, suggesting an important role for SHP-1. Moreover, crocin downregulated the expression of STAT3-regulated anti-apoptotic (Bcl-2, survivin), proliferative (cyclin D1), invasive (CXCR4) and angiogenic (VEGF) proteins. Conversely, crocin increased the pro-apoptotic (BAX) protein, which was correlated with the induction of apoptosis and inhibition of proliferation. Overall, these results provide evidence that crocin has the potential for anticancer activity through inhibition of the IL-6/STAT3 signaling pathway, especially in liver cancer.