ATP-dependent K⁺ (K_ATP) channel function is impaired after fluid percussion brain injury (FPI). Additionally, the nitric oxide (NO) releaser sodium nitroprusside and a cGMP analog elicit pial dilation via K_ATP channel activation, whereas opioids such as methionine enkephalin (Met) elicit pial dilation via NO and K_ATP channel activation. Decremented Met dilation contributes to reductions in pial artery diameter and altered cerebral hemodynamics after FPI. This study was designed to investigate the role of K_ATP channel activation before FPI in the loss of opioid dilation subsequent to FPI in newborn pigs equipped with a closed cranial window. FPI was produced by allowing a pendulum to strike a piston on a saline-filled cylinder that was fluid coupled to the brain via a hollow screw in the cranium. FPI blunted dilation to Met (7 ± 1, 11 ± 1, and 17 ± 1% before FPI vs. 1 ± 1, 4 ± 1, and 6 ± 1% after FPI for 10¹⁰, 10⁸, and 10⁶ M Met, respectively). Met-associated elevation in cerebrospinal fluid (CSF) cGMP was similarly blunted (350 ± 12 and 636 ± 12 fmol/ml before FPI vs. 265 ± 5 and 312 ± 17 fmol/ml after FPI for control and 10⁶ M Met, respectively). In piglets pretreated with cromakalim (10¹⁰ M) 20 min before FPI, Met dilation was partially restored (7 ± 1, 10 ± 1, and 15 ± 1% before FPI vs. 4 ± 1, 7 ± 1, and 11 ± 1% after FPI for 10¹⁰, 10⁸, and 10⁶ M Met, respectively). Met cGMP release was similarly partially restored (400 ± 9 and 665 ± 25 fmol/ml before FPI vs. 327 ± 11 and 564 ± 23 fmol/ml after FPI for control and 10⁶ Met, respectively). Cromakalim (10¹⁰ M) had no effect on pial diameter itself but prevented pial artery constriction by FPI (148 ± 5 to 124 ± 5 µm vs. 139 ± 4 to 141 ± 4 µm in the absence vs. presence of cromakalim pretreatment, respectively). In contrast, pretreatment with a subthreshold concentration of NS-1619, a calcium-dependent K⁺ channel agonist, did not restore vascular and biochemical parameters after FPI. These data indicate that prior K_ATP channel activation reduces the loss of opioid dilation after FPI.