miRNAs, a class of short but stable noncoding RNA molecules, have been revealed to play important roles in the DNA damage response (DDR). However, their functions in cancer genome instability and the consequent clinical effect as the response to chemotherapy have not been fully elucidated. In this study, we utilized multidimensional TCGA data and the known miRNAs involved in DDR to identify a miRNA-regulatory network that responds to DNA damage. Additionally, based on the expression of ten miRNAs in this network, we developed a 10-miRNA-score that predicts defects in the homologous recombination (HR) pathway and genome instability in ovarian cancer. Importantly, consistent with the association between HR defects and improved response to chemotherapeutic agents, the 10-miRNA-score predicts the outcome of ovarian cancer patients treated with platinum agents, with a surprisingly better performance than the indexes of DNA damage. Therefore, our study demonstrates the implication of miRNA expression on cancer genome instability and provides an alternative method to identify DDR defects in patients who show the best effect with platinum drug treatment.