Abstract Under the influence of the COVID-19, people's awareness of physical health and immunity has increased significantly. Chitooligosaccharide is an oligomer of β-(1, 4)-linked D -glucosamine, furthermore, is one of the most widely studied immunomodulators. Chitooligosaccharide can be prepared from the chitin or chitosan polymers through enzymatically, chemically or physically processes. Chitooligosaccharide and its derivatives have been proven to have a wide range of biological activities including intestinal flora regulation, immunostimulant, anti-tumor, anti-obesity and anti-oxidation effects. This review summarizes the latest research of the preparation methods, biological activities in immunity and safety profiles of Chitooligosaccharide and its derivatives. We recapped the effect mechanisms of Chitooligosaccharide basing on overall immunity. Comparing the effects of Chitooligosaccharide with different molecular weights and degree of aggregation, a reference range for usage has been provided. This may provide a support for the application of Chitooligosaccharide in immune supplements and food. In addition, future research directions are also discussed.