Thyroid papillary carcinoma is the most common type of thyroid malignancy. The mitogen-activated protein kinase signaling cascade is the major pathway involved in thyroid papillary carcinoma and may be regulated by small molecules and transcription factors. Zerumbone is a bioactive compound with multiple pharmacological properties. This study investigated the effects of zerumbone on survival and proliferation of thyroid papillary carcinoma-1 cells with an emphasis on the level of microRNA-758-3p and its target gene, mitogen-activated protein kinase-1. Zerumbone exhibited dose-dependent inhibitory effects on the viability and proliferation of thyroid papillary carcinoma-1 cells. It also gradually elevated the level of microRNA-758-3p but decreased mitogen-activated protein kinase-1 expression in these cells. Mitogen-activated protein kinase-1 has been suggested as a downstream target of microRNA-758-3p and confirmed by dual-reporter luciferase assay. The downregulation of microRNA-758-3p in thyroid papillary carcinoma-1 cells via the transfection with microRNA-758-3p inhibitor reversed the inhibitory effect of zerumbone on mitogen-activated protein kinase-1 expression. Furthermore, the transfection of thyroid papillary carcinoma-1 cells with lentiviral vector overexpressing mitogen-activated protein kinase-1 eliminated the protective effects of zerumbone on thyroid papillary carcinoma progression as compared to the group delivered with control vector. In conclusion, this study demonstrated that zerumbone inhibited survival and proliferation of thyroid papillary carcinoma-1 cells via suppressing the expression of mitogen-activated protein kinase-1 through microRNA-758-3p. These data suggest the therapeutic potential of zerumbone in thyroid papillary carcinoma treatment.