Melanoma is one of the main malignant tumors in skin and gullets of human and animals. Melanoma incidence has been increasing over the last 20 years, and while it still represents less than 5% of all cutaneous malignancies. Melanoma accounts for the majority of skin cancer deaths, due to its propensity to metastasize. For new therapies to be developed, a better understanding of the genetic landscape and signal pathways are needed. Numerous studies highlighted the importance of NKG2A-HLA-E in tumor immunotherapy and NKG2A has been regarded as a new immune checkpoint, but the function and mechanism of HLA-E in tumor cells have seldom been studied alone. The statistical analysis from publicly available database Oncomine and The Cancer Genome Atlas (TCGA) showed that HLA-E is more highly overexpressed in melanoma, compared to their non-transformed counterparts. In addition, melanoma patients with HLA-E high expression had a worse overall survival rate than the low expression patients, which indicate the important role of HLA-E in melanoma. Qa-1b is the homolog of HLA-E in mice. In this research, the mice melanoma cell line B16-F10 and the established melanoma mice model were used to study the function and mechanism of Qa-1b in melanoma. Interestingly, we found that Qa-1b was highly expressed in B16-F10 comparing with normal mice epidermal cells. The depletion of Qa-1b inhibited B16-F10 cell proliferation and migration in vitro and xenograft tumor formation in vivo. Furthermore, Qa-1b knockdown promoted cell cycle arrest at G0/G1 phase and cell apoptosis. The results suggested an oncogenic role of Qa-1b in melanoma progression, indicating that Qa-1b could be used as a new therapeutic target in melanoma.