Nicorandil (NIC), an antianginal agent that acts both as an opener of adenosine triphosphate-sensitive potassium (KATP) channels and a nitric oxide donor, has demonstrated protective and curative effects in various diseases. The predominance of these mechanisms varies based on the dose of NIC and the specific organ affected. This study scrutinized the possible beneficial effects of NIC in acetaminophen (APAP)-induced hepatic encephalopathy (HE) model through highlighting the role of KATP channels in mediating these effects. Forty-eight mice were randomly subdivided into four groups: control (saline), APAP model (1 g/kg, i.p.), NIC treatment (15 mg/kg/day p.o. for 14 days), and glibenclamide (GLIB "KATP blocker", 5 mg/kg/day, p.o. 1 h before NIC for 14 days). NIC significantly mitigated APAP-induced liver injury, hyperammonemia, and cognitive deficits, as evidenced by reduced serum alanine aminotransferase, aspartate aminotransferase, ammonia levels, and improved performance in Y-maze and Morris Water Maze tests. Mechanistically, NIC suppressed hippocampal glutamate, activated phosphoserine 473 protein kinase B (p-AKT(Ser473))/mammalian target of rapamycin complex 1 (mTORC1) pathway, lessened the inactive phosphorylation of eukaryotic elongation factor 2 (eEF2), upsurged brain-derived neurotrophic factor (BDNF), leading to reduced neuroinflammation proved by nuclear factor-kappa B and tumor necrosis factor-alpha suppression. Histopathological analyses revealed improved liver and hippocampal morphology, while immunohistochemistry showed reduced astrocyte activation with NIC treatment. These effects were abolished by GLIB pre-treatment, indicating the crucial role of KATP channel. Accordingly, NIC could alleviate APAP-induced liver injury and HE mainly dependent on KATP channel opening, with resultant inhibition of glutamate signaling, activation of p-AKT/mTORC1/eEF2/BDNF trajectory, and abating hippocampal inflammation.