Hyperglycemia‐related neuronal excitability and epileptic seizures are not uncommon in clinical practice. However, their underlying mechanism remains elusive. ATP‐sensitive K⁺ (K_ATP) channels are found in many excitable cells, including cardiac myocytes, pancreatic β cells, and neurons. These channels provide a link between the electrical activity of cell membranes and cellular metabolism. We investigated the effects of higher extracellular glucose on hippocampal K_ATP channel activities and neuronal excitability. The cell‐attached patch‐clamp configuration on cultured hippocampal cells and a novel multielectrode recording system on hippocampal slices were employed. In addition, a simulation modeling hippocampal CA3 pyramidal neurons (Pinsky‐Rinzel model) was analyzed to investigate the role of K_ATP channels in the firing of simulated action potentials. We found that incremental extracellular glucose could attenuate the activities of hippocampal K_ATP channels. The effect was concentration dependent and involved mainly in open probabilities, not single‐channel conductance. Additionally, higher levels of extracellular glucose could enhance neuropropagation; this could be attenuated by diazoxide, a K_ATP channel agonist. In simulations, high levels of intracellular ATP, used to mimic increased extracellular glucose or reduced conductance of K_ATP channels, enhanced the firing of action potentials in model neurons. The stochastic increases in intracellular ATP levels also demonstrated an irregular and clustered neuronal firing pattern. This phenomenon of K_ATP channel attenuation could be one of the underlying mechanisms of glucose‐related neuronal hyperexcitability and propagation. © 2007 Wiley‐Liss, Inc.