Limonin is a natural compound which is rich in the fruit of various plants of the Rutaceae family and demonstrated to have a wide range of biological activities. In this work, seven limonin derivatives were successfully synthesized by hydrogenation of limonin, using different reducing agents (sodium cyanoborohydride, lithium aluminum hydride, and sodium borohydride). The chemical structure of the seven derivatives was characterized and identified by a series of techniques, including HR-ESI-MS, 1H-NMR, 13C-NMR, 2D-NMR, and IR. Among the seven limonin derivatives, six limonin derivatives were found to be new compounds which have not been previously reported. Then, the anti-inflammatory activities of the seven synthesized limonin derivatives, as well as the anti-inflammatory activities of eight known natural limonins, were evaluated and compared. Natural limonins, 30-O-Acetylhainangranatumin E and Xylogranatin A, presented significantly better anti-inflammatory activity. Xylogranatin A could inhibit LPS-induced RAW264.7 cell inflammatory factors, with a 90.0% inhibition ratio of TNF-α and 63.77% inhibition ratio of NO release in LPS-induced BV2 cells at 10 μM. Other natural limonins showed poor anti-inflammatory activity. In comparison, all the synthetic limonin derivatives showed decent anti-inflammatory activities, with the highest inhibition ratio of TNF-α of 37.8% and inhibition ratio of NO release of 12.5% in LPS-induced BV2 cells at 10 μM.