Introduction: Studies have indicated that diabetes mellitus impairs hippocampus. Diabetes increases the risk of depression and treatment with antidepressants may affect learning and memory. The aim of this study was to evaluate the effects of amitriptyline and fluoxetine on synaptic plasticity and TNF-α level in the hippocampus of streptozotocin-induced diabetic rats. Methods: Experimental groups were control, diabetes, diabetes-amitriptyline and diabetes-fluoxetine (n=8 for each experimental group). Three weeks after the induction of diabetes, the rats received treatment with amitriptyline (5 mg/kg) or fluoxetine (5 mg/kg) for 21 days. Long-term potentiation (LTP) in perforant path-dentate gyrus synapses was assessed (by 400 Hz tetanization) for investigating the effect of treatments on synaptic plasticity. Field excitatory post-synaptic potential indices were measured. Finally, TNF-α levels were measured in hippocampus by enzyme-linked immunosorbant assay. Results: Six weeks after the diabetes induction, LTP wasn’t different between the control and the diabetes groups and also no significant differences were observed between the diabetes and the diabetes-treated groups; however, amitriptyline and fluoxetine impaired LTP in diabetic rats and there was a significant difference between the control and the diabetes-treated groups. Comparing to the controls, TNF-α level was increased significantly (P<0.05) only in the diabetes-amitriptyline group. Conclusion: Results suggest that amitriptyline and fluoxetine intensify the destructive effects of diabetes on hippocampus and that TNF-α may act as a mediator for these changes; however, other factors may also be involved. Hence, treatment of diabetic patients with antidepressants must be done with extra care.