Although migraine is a major global public health problem, its impact on cognitive abilities remains controversial. Thus, the present study investigated the effects of repeated administration of inflammatory soup (IS) to the dura of rats, over 3 weeks, on spatial cognition, hippocampal synaptic plasticity, and the expression of N-methyl-D-aspartate receptor (NMDAR) subunits. Additionally, low doses of amitriptyline (AMI; 5 mg/kg) were applied to assess its therapeutic effects. The IS group exhibited significant reductions in the cutaneous stimulation threshold, presence of mild cognitive impairment, and decreased long-term potentiation (LTP) in right hippocampus. However, AMI improved pain behaviors, enhanced cognitive function, and increased synaptic plasticity in the IS rats. On the other hand, the administration of AMI to normal rats negatively influenced synaptic plasticity and reduced the expression of NMDAR subunits. The present results indicate that IS-induced dural nociception led to impairments in spatial cognition that could be attributed to reductions in hippocampal LTP and the decreased expression of NMDAR subunits.