Breast cancer (BC) is the most common cancer affecting women and the leading cause of cancer-related deaths worldwide. Compelling evidence indicates that microRNAs (miRNAs) are inextricably involved in the development of cancer. Here, we constructed a novel model, based on miRNA-seq and clinical data downloaded from The Cancer Genome Atlas (TCGA). Data from a total of 962 patients were included in this study, and the relationships among their clinicopathological features, survival, and miRNA-seq expression levels were analyzed. Hsa-miR-186 and hsa-miR-361 were identified as internal reference miRNAs and used to normalize miRNA expression data. A five-miRNA signature, constructed using univariate and multivariate Cox regression, was significantly associated with disease-specific survival (DSS) of patients with BC. Kaplan-Meier (KM) and receiver operating characteristic (ROC) analyses were conducted to confirm the clinical significance of the five-miRNA signature. Finally, a nomogram was constructed based on the five-miRNA signature to evaluate its clinical value. Cox regression analysis revealed that a five-miRNA signature was significantly associated with DSS of patients with BC. KM analysis demonstrated that the signature could efficiently distinguish high- and low-risk patients. Moreover, ROC analysis showed that the five-miRNA signature exhibited high sensitivity and specificity in predicting the prognosis of patients with BC. Patients in the high-risk subgroup who received adjuvant chemotherapy had a significantly lower incidence of mortality than those who did not. A nomogram constructed based on the five-miRNA signature was effective in predicting 5-year DSS. This study presents a novel five-miRNA signature as a reliable prognostic tool to predict DSS and provide theoretical reference significance for individualized clinical decisions for patients with BC.