Abstract There has been limited research on the preparation of analogues of cycloartane‐type sapogenols (9,19‐cyclolanostanes). Therefore, we decided to use cycloastragenol as a lead compound for structural modification. The semi‐synthetic derivatives were mainly obtained by reactions such as oxidation, alkylation, acylation, and aldol reactions. In this study, we synthesized 27 cycloastragenol derivatives, 20 of which were novel compounds, and evaluated their protective activity on t‐BHP‐induced C2C12 cell growth inhibition and anti‐aging activities. We found that most derivatives inhibited t‐BHP‐induced cell damage. And certain derivatives reduced the formation of ROS and decreased the production of MDA induced by t‐BHP. The findings indicate that these cycloastragenol derivatives might be useful in the treatment of age‐related diseases.