Melanoma causes the highest mortality rate among all skin cancers. However, the underlying molecular mechanisms leading to metastasis and poor prognosis in melanoma have not been fully elucidated. In this study, the differentially expressed genes (DEGs) related to metastasis in melanoma were screened out. The results of gene annotation was combined with The Cancer Genome Atlas (TCGA) database. The microRNA (miRNA) network that regulates key genes and their correlation with BRAFV600E was preliminarily analyzed. Cell and molecular biology experiments were conducted to verify the results of bioinformatics analysis. Results showed that the PI3K-Akt signaling pathway contained the key genes CDK2, CDK4, KIT, and Von Willebrand factor. Survival analysis showed that high expression of the four key genes significantly reduced the survival rate of patients with melanoma. Correlation analysis showed that BRAFV600E may regulate the expression of the four key genes, and a total of 240 miRNAs may regulate this expression. Experiments showed that the inactivation of key genes inhibits the proliferation, migration, and invasion of melanoma. In conclusion, the PI3K-Akt signaling pathway and the four key genes promoted the proliferation, migration, and invasion of melanoma, and related to poor prognosis of patients with melanoma.