Introduction: Stress is associated with neurological and cognitive disorders. It has been suggested that doxepin, in addition to its influence on the content of neurotransmitters, has probable neuroprotective effects as well. Therefore, the aim of this study was to investigate the effects of doxepin on synaptic plasticity and brain-derived neurotrophic factor (BDNF) gene expression in the rat hippocampus following repeated restraint stress. Methods: Male Wistar rats were divided into the control, the stress and the stress-doxepin 1 and 5 mg/kg groups. Stress was induced 6 hours/day for 21 days. Rats received daily ip injection of doxepin before induction of stress. Long-term potentiation (LTP) was induced in hippocampal dentate gyrus following stimulation of perforant pathway and then field excitatory postsynaptic potential was evaluated. Hippocampal gene expression of BDNF was measured by Real-Time PCR. Results: Stress impaired LTP induction, but both doses of doxepin prevented those damages. Stress significantly decreased the expression of BDNF gene, but doxepin in both doses, increased it significantly. Conclusion: The present results suggested that doxepin can prevented the harmful effects of stress on synaptic plasticity which may be related to changes in BDNF gene expression.