Salidroside (Sal) is a natural antioxidant extracted from the root of Rhodiola rosea L., a traditional Chinese medicinal plant, which elicits neuroprotective effects in the treatment of ischemic stroke. In an attempt to improve its neuroprotective effects, fluorine substituted Sal analogues were synthesized and their neuroprotective activities against the hypoglycemia and serum limitation induced cell injury in differentiated PC12 cells were evaluated. The target compounds displayed strong protective effects on the cell viability against the damage caused by hypoglycemia and serum limitation, especially for D1, which had a great potency superior to Sal and efficiently inhibited hypoglycemia and serum limitation induced cell nuclear morphologic changes and the increased apoptotic rate in a dose-dependent manner. These new findings may provide potentially important information for further development of Sal analogues and lay the basis for further studies on the cerebral ischemic stroke and neurodegenerative diseases for human clinical treatment.