S100A12 belongs to the S100 family and acts as a vital regulator in different types of tumors. However, the function of S100A12 in thyroid carcinoma has not yet been investigated. In this study, we analyzed the expression of S100A12 in human papillary thyroid cancer (PTC) samples and two PTC cell lines. In addition, we explored the effects of S100A12 on PTC cell progression in vitro and in vivo. Our results showed that S100A12 was significantly upregulated in PTC specimens. Moreover, silencing S100A12 markedly inhibited PTC cell proliferation, migration, invasion and cell cycle progression. In addition, knockdown of S100A12 significantly reduced the expression of CyclinD1, CDK4 and p-ERK in PTC cells. An in vivo study also showed that silencing S100A12 dramatically suppressed tumor cell growth and decreased Ki67 expression in a xenograft mouse model. This study provides novel evidence that S100A12 serves as an oncogene in PTC. Knockdown of S100A12 suppressed PTC cell proliferation, migration, and invasion and induced G0/G1 phase arrest via the inhibition of the ERK signaling pathway. Therefore, S100A12 may be a potent therapeutic target for PTC.