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Genomic instability is one of the main drivers of tumorigenesis and the development of hematological malignancies. Cancer cells can remedy chemotherapeutic-induced DNA damage by upregulating DNA-repair genes and ultimately inducing therapy resistance. Nevertheless, the association between the DNA-repair genes, drug resistance, and disease relapse has not been well characterized in acute lymphoblastic leukemia (ALL). This study aimed to explore the role of the DNA-repair machinery and the molecular mechanisms by which it is regulated in early- and late-relapsing pediatric ALL patients. We performed secondary data analysis on the Therapeutically Applicable Research to Generate Effective Treatments (TARGET)—ALL expansion phase II trial of 198 relapsed pediatric precursor B-cell ALL. Comprehensive genetic and epigenetic investigations of 147 DNA-repair genes were conducted in the study. Gene expression was assessed using Microarray and RNA-sequencing platforms. Genomic alternations, methylation status, and miRNA transcriptome were investigated for the candidate DNA-repair genes. We identified three DNA-repair genes, <i>ALKBH3</i>, <i>NHEJ1</i>, and <i>PARP1</i>, that were upregulated in early relapsers compared to late relapsers (<i>p</i> < 0.05). Such upregulation at diagnosis was significantly associated with disease-free survival and overall survival in precursor-B-ALL (<i>p</i> < 0.05). Moreover, <i>PARP1</i> upregulation accompanied a significant downregulation of its targeting miRNA, miR-1301-3<i>p</i> (<i>p</i> = 0.0152), which was strongly linked with poorer disease-free and overall survivals. Upregulation of DNA-repair genes, <i>PARP1</i> in particular, increases the likelihood of early relapse of precursor-B-ALL in children. The observation that <i>PARP1</i> was upregulated in early relapsers relative to late relapsers might serve as a valid rationale for proposing alternative treatment approaches, such as using PARP inhibitors with chemotherapy.