ABSTRACTMelanoma with rapid progression towards metastasis becomes the deadliest form of skin cancer. However, the mechanism of melanoma growth and metastasis is still unclear. Here, we found that miRNA-138 was low expression and hypoxia-inducible factor 1α (HIF1α) was high expression in the patient’s melanoma tissue, and they had a significant negative correlation (r = -0.937, P < 0.001). Patients with miRNA-138low/HIF1αhigh signature were predominant in late stage. Further, bioinformatic analysis demonstrated that miRNA-138 directly targeted HIF1α. We found that the introduction of miRNA-138 mimics to A375 cells could reduced HIF1α mRNA expression, and suppressed the cell proliferation, migration and invasion. Overexpression of miRNA-138 or inhibition of HIF1α significantly suppressed the growth and metastasis of melanoma in vivo. Our study demonstrates the role and clinical relevance of miRNA-138 and HIF1α in melanoma cell growth and metastasis, providing a novel therapeutic target for suppression of melanoma growth and metastasis.