Description. Cutaneous melanoma (SKCM) is one of the most common skin malignancies. miR-100-5 has been found to highly express microRNAs in a variety of cancers. This is a novel biomarker to inhibit the proliferation, migration, and invasion of cutaneous melanoma. However, its function and potential mechanisms in SKCM remain unknown. Objective. To better understand the role and underlying mechanisms of SKCM, we conducted bioinformatics analysis and in vivo experiments. Results. We found its role as a tumor suppressor gene in SKCM and its effect on prognosis. In addition, this study found that miR-100-5p had a bidirectional effect on SKCM microenvironment. After exploring the relationship between the two, it was found that tumors with intermediate miR-100-5p expression had the highest level of immune cell infiltration. In addition, the value of miR-100-5p was assessed by survival analysis, univariate Cox regression analysis, and nomogram prognostic prediction. Finally, we constructed a regulatory network to illustrate the regulatory relationship of miR-100-5p. Conclusions. In conclusion, the antitumor effect of miR-100-5p is revealed, and the present study is followed by a discussion of its molecular regulatory network, followed by novel insights into SKCM therapy.