Driven by energy demand and environmental safety, the ability to treat and dispose of nuclear waste is sought to fulfil the demand for sustainable nuclear power. Radioactive byproducts generated by nuclear fission, including cationic radionuclides (235UO22+, 137Cs+, 90Sr2+, noble metals and partial actinide elements), anionic radionuclides (99TcO4−, 129/131I3−, 129/131I−, etc.), gaseous effluents (129/131I2, 85Kr, 127Xe, 222Rn, etc.), and tritium, should be managed safely and efficiently, underscoring the need for robust scientific solutions to minimize environmental contamination and foster public confidence. For this purpose, framework materials like metal–organic frameworks (MOFs), covalent organic frameworks (COFs), hydrogen-bonded organic frameworks (HOFs), supramolecular assembly frameworks (SAFs) and porous aromatic frameworks (PAFs) have emerged as highly promising platforms for radionuclide extraction and removal relying on their unique properties of abundant structures, customizable functionality, tunable pore sizes, and high specific surface area. Thus far, there is a lack of a comprehensive review that systematically integrates materials design, research progress, and practical applications for achieving comprehensive radionuclide separation. This review begins with a comprehensive overview of the scientific significance and structural characteristics of framework materials, followed by a summary of their design principles, synthetic strategies, and functional versatility. It then presents a detailed examination of recent applications across various radionuclide classes, with an in-depth discussion of advanced design paradigms, performance across diverse scenarios, and mechanisms. Finally, future perspectives are outlined to address unresolved scientific and technical challenges and to accelerate the practical implementation of next-generation framework materials. This work provides a foundational platform for engineering innovation and the broader application of framework materials, which is crucial for the effective and sustainable management of nuclear waste.