Background <p>Radioresistance is a major challenge in the treatment of patients with colorectal cancer (CRC) and impairs the efficacy of radiotherapy. The PI3K/AKT/mTOR signaling pathway plays a critical role in CRC and contributes to the development of radioresistance. Accordingly, targeting this signaling pathway may be a promising strategy to improve oncotherapy.</p> Methods <p>We performed a systematic search of Scopus, PubMed, Web of Science, Embase, and Medline databases. We included articles that investigated the effects of PI3K/AKT/mTOR pathway inhibitors on improving the efficacy of radiotherapy.</p> Result <p>Of the 32 articles included in our review, 27 were preclinical studies and 5 were clinical trials. We examined the effects of various signaling pathway inhibitors in combination with radiotherapy. While the efficacy of these therapies when used alone is limited, their combination is associated with reduced survival, induction of apoptosis, and cell cycle arrest, which may increase radiosensitivity. Despite the limited number of studies, this combination therapy has shown favorable treatment outcomes in patients with CRC.</p> Conclusion <p>PI3K/AKT/mTOR is a critical signaling pathway for cancer cell survival. By inhibiting this pathway, we can increase the efficacy of radiotherapy. These results provide valuable insights for the further development of research and clinical practice in the treatment of colorectal cancer.</p> Graphical Abstract <p></p>