Propofol can induce acute neuronal apoptosis or long-term cognitive dysfunction when exposed at early age in rodents, but it is unclear how the neurotoxicity including neuronal apoptosis and synaptic loss will change in a dynamic manner with brain development after multiple or single exposure of propofol, and the role of neuronal apoptosis and synaptic loss in propofol-induced long-term cognitive impairment needs to be elucidated. In this study, we investigated dynamic changes of neuronal apoptosis, neuronal density, synaptic density in hippocampal CA1 region and the prelimbic cortex (PrL), and long-term cognitive function after multiple or single exposure of propofol in neonatal rats. Results showed that single exposure of propofol only induced great neuronal apoptosis and deficit at postnatal day 9(P9); while multiple exposures of propofol could induce significant neuronal apoptosis, neuronal deficit and synaptic loss at P9, P14, P21, or P35 compared with intact, and spatial learning and memory impairment from P36 to P41. Results suggest that single exposure of propofol only induces transient neuronal apoptosis and deficit, while multiple exposures of propofol induce persistent neuronal apoptosis, neuronal deficit, synaptic loss, and long-term cognitive impairment. Furthermore, persistent neuronal deficit and disturbances in synapse formation but not transient neuronal apoptosis may contribute to long-term cognitive impairment.