Sorafenib was originally identified as an inhibitor of multiple oncogenic kinases and remains the first-line systemic therapy for advanced hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) have been reported to play critical roles in the initiation, progression, and drug resistance of HCC. In this study, we aimed to identify sorafenib-induced miRNAs and demonstrate their regulatory roles. First, we identified that the expression of the tumor-suppressive miRNA miR-375 was significantly induced in hepatoma cells treated with sorafenib, and miR-375 could exert its antiangiogenic effect partially via platelet-derived growth factor C (PDGFC) inhibition. Then, we demonstrated that sorafenib inhibited PDGFC expression by inducing the expression of miR-375 and a transcription factor, achaete-scute homolog-1 (ASH1), mediated the induction of miR-375 by sorafeinb administration in hepatoma cells. Finally, we verified that the expression of miR-375 was reduced in sorafenib-resistant cells and that the restoration of miR-375 could resensitize sorafenib-resistant cells to sorafenib partially by the degradation of astrocyte elevated gene-1 (AEG-1). In conclusion, our data demonstrate that miR-375 is a critical determinant of HCC angiogenesis and sorafenib tolerance, revealing a novel miRNA-mediated mechanism underlying sorafenib treatment.