Earthworms have been used in traditional medicine for thousands of years. Current studies have revealed that they may offer therapeutic benefits for various diseases, including hypertension, diabetes, and cancer. Current research primarily focuses on investigating the bioactivity of earthworm extracts and analyzing earthworm proteins, and earthworm peptides. This study summarized the bioactivities and mechanisms of these earthworm-derived substances in diseases treatment over the past decades, aiming to provide directions for further in-depth research and the application of earthworm-derived bioactive substances in the biological and pharmaceutical fields.