MAL2, a member of the MAL proteolipid family, is essential for raft-mediated transport. In this study, we investigated the roles and underlying mechanism of MAL2 in the development of papillary thyroid carcinoma (PTC). Up-regulation of MAL2 was found in human PTC tissues and significantly correlated with poor overall survival (OS). Knockdown of MAL2 dramatically suppressed PTC cell proliferation and invasion in vitro and inhibited tumor growth in vivo. We further found that miR-129 suppressed the expression of MLA through directly binding to the 3′ untranslated region (3′ UTR). While forced miR-129 expression suppressed growth and invasion of PTC cells, re-expression of MAL2 rescued these effects. Taken together, our data indicated that MAL2 acted as an oncogene and was negatively regulated by miR-129, supporting the potential therapeutic strategy against PTC by targeting miR-129-MAL2 axis.