Escalating evidence suggests that microRNA-101 (miR-101) is implicated in the development and progression of various cancers, including papillary thyroid carcinoma (PTC). However, the biological function and molecular mechanisms of miR-101 in PTC are still unclear. In this study, we demonstrated that miR-101 expression was significantly decreased in PTC tissues and cell lines. Clinically, a low level of miR-101 was positively associated with advanced histological stages and lymph node and distant metastases. The expression of CXCL12 was negatively correlated with miR-101 level in PTC. CXCL12 was validated as a direct target of miR-101 in PTC cells. Functional experiments proved that miR-101 markedly reduced the proliferation, apoptosis escape, migration, and invasion of PTC cells. Moreover, CXCL12 restoration rescued the suppressive effects of miR-101 on PTC cells by activating Akt- and EMT-associated signaling pathways. Overall, miR-101 exerts oncostatic effects on PTC by downregulating CXCL12 and repressing its downstream Akt and Snail signaling pathways, suggesting that miR-101/CXCL12/Akt or Snail axis may serve as a potential therapeutic target for PTC.