Vasculogenic mimicry (VM) is an alternative type of blood supplement and is responsible for aggressive tumor biology and increased tumor-related mortality. Tumor cells obtain oxygen and nutriment through VM channels in the early, rapid-growth stage when blood vessels are insufficient. VM channels are characterized by tubular structures with tumor cells. Autophagy is a catabolic process, by which the cell digests damaged components or organelles of its own cytoplasm in response to nutrient deprivation, hypoxia, and the presence of non-functional protein aggregates. In fact, autophagy plays an important role in normal cell growth, development, and homeostasis. However, it is still controversial whether autophagy is also involved in cell death or cell survival in malignancy. In the present study, we therefore investigated the expression levels of two autophagy-related proteins, microtubule-associated protein-1 light chain 3 (LC3) and beclin-1, with respect to melanoma metastasis and vasculogenic mimicry. Melanoma is characterized by rapid growth, high-metastasis rate, and unpredictable behavior. A total of 70 human melanoma tissues were analyzed, showing that VM was present in 31 melanoma specimens (44.3%). Melanoma cells displayed high levels of autophagy when VM was present. Real-time quantitative PCR and immunohistochemical analyses showed that the expression levels of beclin-1 and LC3 mRNAs and proteins were both higher in the VM-positive melanoma than those in the VM-negative melanoma (p < 0.05). Moreover, the expression of LC3, rather than beclin-1, was strongly associated with metastasis and poor clinical prognosis of human melanoma. Therefore, the enhanced autophagic activity may be related to VM and metastasis of melanoma.