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Chemoresistance represents a significant challenge in the chemotherapy of colorectal cancer (CRC), limiting the effectiveness. In this regard, gene expression heterogeneity plays a critical role, influencing cancer cell adaptability and survival under chemotherapy. Our previous data revealed that ribosomal protein uL3 positively correlates with both chemoresistance and poor prognosis in CRC patients. This study explores the combination of 5-fluorouracil (5-FU), the first-line treatment of CRC, with G-quadruplex (G4) ligands, which have recently emerged as promising candidates for cancer therapy, to overcome uL3-mediated chemoresistance. We found that resistant p53-deficient and uL3-silenced CRC cells showed increased levels of G4 structures compared to both sensitive p53-deficient and p53-proficient cells, thereby exhibiting vulnerability to the cytotoxic effects of two well-established G4 ligands, pyridostatin (PDS) and RHPS4. The combination of 5-FU with PDS or RHPS4 exhibited a synergistic effect, selectively targeting tumor cells. This approach enabled a >10-fold reduction in the 5-FU dose, improving treatment efficacy. The effectiveness of this combination was further validated in vivo using uL3-silenced CRC cell-derived xenografts in a chicken embryo model. Overall, our findings highlight a novel and promising combination strategy that targets chemoresistance in CRCs characterized by non-functional p53 and reduced levels of uL3.