Melanoma is a highly metastatic cancer that requires effective and targeted curative therapy. Annexin A10 (ANXA10), a member of the annexin family, is a calcium- and phospholipid-binding protein. Considerable evidence indicates that ANXA10 is involved in tumour progression, but little is known about its role in melanoma development. In this study, we find that ANXA10 expression is significantly upregulated, and correlates with melanoma progression. ANXA10 knockout profoundly reduces cell migration and the metastatic activity of melanoma. In addition, ANXA10 knockout induces the N- to E-cadherin switch by upregulating SMAD6, an inhibitory SMAD in the TGF-β/SMAD pathway. The negative regulation of SMAD6 by ANXA10 is dependent on PKD1. ANXA10 interacts with PKD1 and inhibits E3 ligase TRIM41-targeted PKD1 degradation. In B16F10 melanoma cells, protein levels of ANXA10 and PKD1 are inversely correlated with SMAD6 level, but correlated with cell migration. Interestingly, ANXA10 and SMAD6 levels are inversely correlated in clinical samples of melanoma progression. Our findings suggest that the ANXA10-PKD1-SMAD6 axis is a new target for therapeutic strategies against melanoma metastasis.