Melanoma is considered as one of the most invasion types of skin cancer with high mortality rates. Although combination of immune checkpoint therapy with local surgical excision provide a novel promising therapeutic strategies, the overall prognosis of melanoma patients remains unsatisfactory. Endoplasmic reticulum (ER) stress, a process of protein misfolding and undue accumulation, has been proven to play an indispensable regulatory role in tumor progression and tumor immunity. However, whether the signature based ER genes has predictive value for the prognosis and immunotherapy of melanoma has not been systematically manifested. In this study, the LASSO regression and multivariate Cox regression were applied to construct a novel signature for predicting melanoma prognosis both in the training and testing set. Intriguingly, we found that patients endowed with high- and low-risk scores displayed differences in clinicopathologic classification, immune cell infiltration level, tumor microenvironment, and immune checkpoint treatment response. Subsequently, based on molecular biology experiments, we validated that silencing the expression of RAC1, an ERG composed of the risk signature, could restrain the proliferation and migration, promote apoptosis, as well as increase the expression of PD-1/PD-L1 and CTLA4 in melanoma cells. Taken together, the risk signature was regarded as promising predictors for melanoma prognosis and might provide prospective strategies to ameliorate patients’ response to immunotherapy.