The integration of microRNAs (miRNAs) with radiotherapy represents a novel paradigm in oncological treatment, aiming to enhance therapeutic efficacy while mitigating radiation resistance. miRNAs are small, noncoding RNA molecules that regulate gene expression posttranscriptionally and play a crucial role in modulating tumor radio sensitivity. Certain miRNAs act as radiosensitizers, enhancing radiation-induced apoptosis by targeting key regulators of DNA repair and cell survival. Notable examples include miR-34a, which suppresses DNA repair pathways and induces apoptosis through p53 activation, and miR-16, which downregulates Bcl-2, promoting radiation-induced cell death. Conversely, miRNA that confers radio-resistance, such as miR-210, miR-221/222, and miR-155, facilitate tumor cell survival by enhancing DNA damage repair, modulating hypoxia-associated signaling, and regulating inflammatory responses. The clinical application of miRNA-based therapy involves the use of miRNA mimics to enhance radiosensitivity and antagomirs to inhibit radio-resistance mechanisms. Additionally, nanoparticle-based delivery systems are being optimized to enhance stability, bioavailability, and targeted delivery of miRNA therapeutics. Besides, miRNAs hold promise as biomarkers for predicting radiotherapy outcomes, enabling more precise and individualized treatment strategies. However, critical challenges, including efficient delivery, off-target effects, and clinical validation, must be addressed. Rigorous preclinical and clinical investigations are essential to optimize the therapeutic feasibility and translational potential of miRNA-based radio-sensitization strategies, paving the way for their clinical implementation.