Amnestic mild cognitive impairment (aMCI) is associated with increased activation in the CA3-dentate region of hippocampus. Excess CA3 activity also occurs in aged rats with memory impairment. Therapies to counter such excess activity might include antiepileptics or agonists for GABAAα5 receptors, which regulate tonic inhibition. Use of GABAAα5 agonists may seem unexpected because GABAAα5 inverse agonists were developed as cognitive enhancers. We found that inverse agonists, while yielding benefit in normal young adult rats, are not effective in treating memory loss in aged rats. Instead, aged rats showed improved memory after treatment with selective GABAAα5 agonists and with certain antiepileptics. These benefits of treatment are consistent with the concept that excess activity in the CA3 of the hippocampus is a dysfunctional condition contributing to age-associated memory impairment. Because excess hippocampal activation is also observed in aMCI, our findings support the use of antiepileptic or GABAAα5 agonist therapy in aMCI. Such therapy, in addition to memory improvement, may also have disease modifying potential because hippocampal overactivity in aging/MCI predicts further cognitive decline and conversion to Alzheimer’s disease.