Cellulose-based aerogels (CBAs) are advanced functional materials characterized by ultra-low density, high porosity, biocompatibility, biodegradability, and renewability. Their versatile porous architecture and abundant hydroxyl groups enable precise functional tailoring. This chapter reviews key functionalization strategies for CBAs, including physical modifications, chemical modifications (such as oxidation, esterification, etherification, grafting, and cross-linking), in situ hybridization with functional nanoparticles, and compound functionalization approaches. These techniques enable multi-component synergy, enhanced reactivity, and improved biological activity, transforming CBAs into intelligent platforms with extended high-performance functionalities. Applications of functionalized CBAs are diverse, spanning thermal insulation, oil–water separation and adsorption, atmospheric water harvesting, CO₂ capture, electromagnetic interference shielding, energy storage and conversion, catalysis, and biomedical uses. Despite these advancements, several challenges remain, including the development of stimuli-responsive systems, green and scalable fabrication methods, in-depth biocompatibility assessments, standardized clinical translation pathways, and integration with AI-assisted design tools. Addressing these issues is essential to fully unlock the potential of CBAs in environmental, energy, electronic, and biomedical applications.