Background: Ginsenoside Rg1 is the primary bioactive component of ginseng, which is a famous traditional Chinese medicine used to treat ischemic cardiovascular and cerebrovascular diseases. It has demonstrated considerable protective effects in neurons injured by ischemia/reperfusion both in in vitro and in vivoconditions. However, the effect and mechanism of action of ginsenoside Rg1 on the neural synaptic plasticity injured by ischemia/reperfusion have not yet been clarified. Objective: In this study, we aim to establish the model of oxygen–glucose deprivation/reoxygenation (OGD/R)-injured primary cortical neurons to mimic ischemia/reperfusion injury and investigate the mechanisms of action of ginsenoside Rg1 on the neural synaptic plasticity. Materials and Methods: Protective effects of ginsenoside Rg1 on neurons after OGD/R injury were measured by cell counting kit-8, lactate dehydrogenase, and apoptosis assay. The mRNA expression and activity of growth associated protein (GAP)-43, microtubule-associated protein (MAP)-2, Tau, insulin like growth factors (IGF)-1, brain derived neurotrophic factor (BDNF), and vascular endothelial growth facto r (VEGF) in neurons after OGD/R injury were measured by real-time polymerase chain reaction (RT-PCR) or enzyme-linked immunosorbent assay. The expression of apoptosis-related genes and cytosolic Ca2+ levels in neurons were determined via RT-PCR or Rhod-2 fluorescence staining. Results: According to our results, ginsenoside Rg1 protected the neurons and promoted axonal regeneration and neuronal remodeling after OGD/R injury; increased the expression of GAP-43, MAP-2, Tau, IGF-1, BDNF, VEGF, and Bcl-2 and inhibited the expression of Bax; and decreased the intracellular Ca2+ overload in OGD/R-injured neurons. Conclusion: Ginsenoside Rg1 can promote axonal regeneration and neuronal remodeling after OGD/R injury by upregulating the expression of synaptic remodeling proteins and endogenous neurotrophic factors, inhibiting intracellular Ca2+ overload and regulating the expression of apoptotic genes.