Radiotherapy remains a cornerstone in cancer treatment, yet its efficiency is often limited by radiation resistance and collateral damage to healthy tissues. Recent advances in nanotechnology offer promising solutions to enhance therapeutic efficacy while minimizing side effects. This study explores the application of gamma-irradiation-enhanced nanocomposites for colorectal cancer therapy. The synthesized nanocomposites, comprising silver-manganese (Ag-Mn) nanoparticles, were structurally characterized using X-ray diffraction (XRD), transmission electron microscopy (TEM), and dynamic light scattering (DLS). Their biocompatibility and radiosensitization potential were evaluated through in vitro assays on colorectal cancer cells (HT-29). Our findings demonstrate that gamma-irradiated Ag-Mn nanocomposites significantly enhance radiation-induced apoptosis by increasing reactive oxygen species (ROS) production and inducing DNA damage in cancer cells. The results suggest that these nanocomposites lower the required radiation dose for effective tumor suppression, potentially reducing radiation-induced toxicity to surrounding healthy tissues. This research aligns with the symposium’s focus on advanced materials for healthcare applications and sustainable technologies in medicine, offering a novel approach to improving cancer treatment outcomes through nanotechnology-enhanced radiotherapy.