Objective: Identifying biomarkers that predict the efficacy and prognosis of chemoradiotherapy is important for individualized clinical treatment. We previously reported that high murine double minute 1 (MDM1) expression in patients with rectal cancer is linked to a favorable chemoradiation response. In this study the role of MDM1 in the chemoradiotherapy response in colorectal cancer (CRC) patients was evaluated. Methods: Colony formation and cell proliferation assays as well as xenograft models were used to determine if MDM1 expression affects the sensitivity of CRC cells to chemoradiation. RNA sequencing revealed that MDM1 regulates tumor protein 53 (TP53) expression and apoptosis. A series of molecular biology experiments were performed to determine how MDM1 affects p53 expression. The effects of inhibitors targeting apoptosis on MDM1 knockout cells were evaluated. Results: Gene expression profiling revealed that MDM1 is a potential chemoradiotherapy sensitivity marker. The sensitivity of CRC cells to chemoradiation treatment decreased after MDM1 knockout and increased after MDM1 overexpression. MDM1 affected p53 expression, thereby regulating apoptosis. MDM1 overexpression limited YBX1 binding to TP53 promoter, regulated TP53 expression, and rendered CRC cells more sensitive to chemoradiation. In CRC cells with low MDM1 expression, a combination of apoptosis-inducing inhibitors and chemoradiation treatment restored sensitivity to cancer therapy. Conclusions: The current study showed that MDM1 expression influences the sensitivity of CRC cells to chemoradiation by influencing p53 and apoptosis pathways, which is the basis for the underlying molecular mechanism, and serves as a possible predictive marker for chemoradiotherapy prognosis.