Ionizing radiation (IR) and cisplatin are frequently used cancer treatments, although the mechanisms of error-prone DNA repair-mediated genomic instability after anticancer treatment are not fully clarified yet. RECQL4 mutations mainly in the C-terminal region of the RECQL4 gene lead to the cancer-predisposing Rothmund-Thomson syndrome, but the function of RECQL4ΔC (C-terminus deleted) in error-prone DNA repair remains unclear. We established several RECQL4ΔC cell lines and found that RECQL4ΔC cancer cells, but not RECQL4ΔC nontumorigenic cells, exhibited IR/cisplatin hypersensitivity. Notably, RECQL4ΔC cancer cells presented increased RPA2/RAD52 foci after cancer treatments. RECQL4ΔC HCT116 cells exhibited increased error-prone single-strand annealing (SSA) activity and decreased alternative end-joining activities, suggesting that RECQL4 regulates the DNA repair pathway choice at double-strand breaks. RAD52 depletion by siRNA or RAD52 inhibitors (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside [AICAR], (-)-epigallocatechin [EGC]) or a RAD52-phenylalanine 79 aptamer significantly restrained the growth of RAD52-upregulated RECQL4ΔC HCT116 cells in vitro and in mouse xenografts. Remarkably, compared to single-agent cisplatin or EGC treatment, cisplatin followed by low-concentration EGC had a significant suppressive effect on RECQL4ΔC HCT116 cell growth in vivo. Together, the regimens targeting the RAD52-mediated SSA pathway after anticancer treatment may be applicable for cancer patients with RECQL4 gene mutations.