The present study investigated the effects of nicorandil on cerebral injury following cardiopulmonary resuscitation (CPR) in a swine model of cardiac arrest. CPR was performed on swine following 4 min induced ventricular fibrillation. Surviving animals were randomly divided into 3 groups: A nicorandil group (n=8), a control group (n=8) and a sham group (n=4). The sham group underwent the same surgical procedure to imitate cardiac arrest, but ventricular fibrillation was not induced. When the earliest observable return of spontaneous circulation (ROSC) was detected, the nicorandil and control groups received injections of nicorandil and saline, respectively. Swine serum was collected at baseline and 5 min, 0.5, 3 and 6 h following ROSC. Serum levels of neuron-specific enolase (NSE), S100ß, tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) were measured using ELISA. Animals were euthanized and brain tissue samples were collected and assessed using light and electron microscopy 6 h following ROSC. The expression of aquaporin-4 (AQP-4) in the brain tissue was measured using western blotting. Malondialdehyde (MDA) and glutathione (GSH) levels in the brain tissue were determined using thiobarbituric acid and thiobenzoic acid colorimetric methods, respectively. Serum NSE and S100ß were significantly higher in the nicorandil and control groups following CPR, compared with baseline (P<0.05). Additionally, NSE and S100ß levels were significantly lower in the nicorandil group compared with the control (P<0.05). Pathological examinations and electron microscopy indicated that nicorandil reduced brain tissue damage. TNF-α and IL-6 levels were significantly decreased in the nicorandil group compared with the control group (P<0.05). Furthermore, AQP-4 expression in brain tissue 6 h following ROSC was significantly lower in the nicorandil group compared with the control group (P<0.05). MDA and GSH levels in swine brain tissue decreased and increased, respectively, in the nicorandil group compared with the control group (P<0.05). The results of the present study demonstrate that nicorandil exerts a protective effect against brain injury following cardiac arrest by reducing oxidative damage, inflammatory responses and brain edema post-ROSC.