MicroRNAs (miRNAs) have drawn enormous attention owing to their significant roles in various biological processes, as well as in the pathogenesis of human diseases. Therefore, predicting miRNA-disease associations is a pivotal task for the early diagnosis and better understanding of disease pathogenesis. To date, numerous computational frameworks have been proposed to identify potential miRNA-disease associations without escalating the costs and time required for clinical experiments. In this regard, I propose a novel computational framework (MDMF) for identifying potential miRNA-disease associations using matrix factorization with a disease similarity constraint. To evaluate the performance of MDMF, I calculated the area under the ROC curve (AUCs) in the framework of global and local leave-one-out cross-validation (LOOCV). In conclusion, MDMF achieved reliable AUC values of 0.9147 and 0.8905 for global and local LOOCV, respectively, which was a significant improvement upon the previous methods. Additionally, case studies were conducted on two major human cancers (breast cancer and lung cancer) to validate the effectiveness of MDMF. Comprehensive experimental results demonstrate that MDMF not only discovers miRNA-disease associations efficiently but also deciphers the underlying roles of miRNAs in the pathogenesis of diseases at a system level.