Abstract: The invention discloses a lenalidomide gastro-retentive sustained-release tablet and a preparation method thereof. The sustained-release tablet comprises 3 wt % to 14 wt % of lenalidomide, 14 wt % to 68 wt % of release enhancer with low bulk density, 23 wt % to 70 wt % of sustained-release material with low bulk density, and the balance of other pharmaceutically acceptable excipients, wherein the bulk density of the release enhancer ranges from 0.24 g/cm3 to 0.52 g/cm3; and the bulk density of the sustained-release material ranges from 0.29 g/cm3 to 0.51 g/cm3. The sustained-release tablet of the invention is in a floating state in a gastric environment, is not directly discharged from a stomach due to gastric emptying, has an effect of gastric retention, and is not easily discharged with substances contained in the stomach, and has a high drug bioavailability and small side effects.