Nanoparticles (NPs) with excellent properties have been rapidly developed and applied in various fields such as phototherapy, early cancer diagnosis, drug carriers, electronic components, cosmetics, food additives, water treatment, and soil remediation. Humans could be directly exposed to these NPs via these applications. These NPs or NP-containing products could also be released into the environment, leading to potential environmental risks. Therefore, the environmental and health risks of nanomaterials urgently need to be assessed, especially for the development of control methodologies. Methods for control or regulation of nanomaterial risks are still in the developmental stages, and some knowledge gaps and ambiguities still exist. To address these knowledge gaps and to guarantee the sustainable development of nanote- chnology, this review discusses the attenuation of nanotoxicity and mechanisms thereof. Physicochemical properties of NPs, such as size, purity, and surface properties (surface charge, hydrophilicity, and surface modification) influence their interactions with biological systems. Environmental conditions during the interaction of NPs with cells, such as exposure dose and time and reaction media, also affect nanotoxicity. Optimization of these physicochemical properties and environmental conditions is expected to aid the design of ideal NPs and control adverse effects of NPs. Nanotoxicity has been reported to be reduced by adjusting size, purity, surface properties (surface charge, hydrophilicity, and surface modification), exposure dose and time, and reaction media of NPs. Herein, the corresponding progress and challenges are also discussed individually. Moreover, this review elaborates on toxic mechanisms and attenuation of nanotoxicity involving five aspects: chemophysiological damage of cellular and subcellular structures, oxidative stress, genes, proteins, and metabolism. Understanding mechanisms underlying the interaction of NPs with biological systems would be conducive to the prediction of nanotoxicity and the design of experiments to attenuate this nanotoxicity. Currently, further studies need be conducted to explore NP uptake, absorption, distribution, interaction, and elimination in biological systems or cells. Globally, the methods of nanotoxicity attenuation remain immature, and well-corroborated methods are unavailable. Finally, perspectives on future research in nanotoxicity attenuation are proposed. An understanding of nanotoxicology and the development of related control methods affect multiple disciplines, including medicine, chemistry, physics, biology, and environmental science. Therefore, multidisciplinary experts need to urgently work together to ensure the sustainable development of nanotechnology.