The hippocampus, one of the most vulnerable regions in the brain, has been implicated in learning and memory formation. However, impairment of hippocampal function is observed during normal aging and neurodegenerative processes. Current evidence suggests that mitochondria and NO participate prominently in cellular signaling in the hippocampus integrating physiologic and toxic pathways. Although all isoforms of nitric oxide synthase are expressed in hippocampal cells, the production of NO in the dependency of glutamate receptors is primarily involved in hippocampal physiopathology. Taking into consideration that the biological impact of NO remains largely qualitative, this review discusses generally the regulation of glutamate-dependent NO production in hippocampus with implications in synaptic plasticity and explores mechanisms by which NO and mitochondria coordinate physiologic and toxic pathways, in particular the excitotoxic NO-mitochondrial connection, the excitotoxic-dependent DNA damage and the mitochondrial biogenesis and trafficking.