Annexin A10 (ANXA10) is a member of annexin A and has been reported to highly express in papillary thyroid carcinoma (PTC) tissues. Tumor susceptibility gene 101 (TSG101) also plays a role in PTC and is predicted to bind to ANXA10. This study intended to investigate whether ANXA10 could regulate PTC via binding to ANXA10. The expression of ANXA10 and TSG101 in normal thyroid follicular epithelial cell line and several PTC cell lines was analyzed using RT-qPCR and western blotting assays. Subsequently, PTC cell line BCPAP was silenced with ANXA10 followed by TSG101 overexpression or not, and then cell proliferation, apoptosis and mitogen-activated protein kinase (MAPK) signaling expression were assessed via MTT, colony formation, immunofluorescence staining, Tunel staining and western blotting assays. Besides, the interaction between ANXA10 and TSG101 was validated using Co-immunoprecipitation assay. ANXA10 and TSG101 expressions were up-regulated in PTC cell lines. ANXA10 silence inhibited proliferation, promoted apoptosis and inactivated MAPK/ extracellular regulated protein kinases (ERK) signaling pathway of BCPAP cells. Additionally, ANXA10 could bind to TSG101 and regulate its expression. However, the above effects of ANXA10 silence on BCPAP cells were all blocked by TSG101 overexpression. ANXA10 inhibited proliferation and promoted apoptosis of PTC cells via binding to TSG101, and these actions may depend on down-regulating MAPK/ERK pathway expression.