Brain injury and cerebral inflammation are frequent complications following cardiopulmonary bypass (CPB) resulting in neurocognitive dysfunction, encephalopathy, or stroke. We compared cerebral inflammation induced by del Nido and histidine-tryptophan-α-ketoglutarate (HTK) cardioplegia in a porcine model. Pigs underwent 90 min cardiac arrest using HTK (n = 9) or Jonosteril^®-based del Nido cardioplegia (n = 9), followed by a 120 min reperfusion. Brain biopsies were collected and analyzed for the mRNA and protein expression of hypoxia-inducible factor-1α (HIF-1α) and cytokines. HTK induced a decrease in blood sodium, chloride, and calcium concentration (cross-clamp aorta: p_sodium < 0.01, p_chloride < 0.01, p_calcium < 0.01; 90 min ischemia: p_sodium < 0.01, p_chloride < 0.01, p_calcium = 0.03) compared to the more stable physiological electrolyte concentrations during del Nido cardioplegia. Hyponatremia and hypochloremia persisted after a 120 min reperfusion in the HTK group (p_sodium < 0.01, p_chloride = 0.04). Compared to del Nido, a higher mRNA expression of the proinflammatory cytokine IL-1β was detected in the frontal cortex (HTK: ∆Ct 6.5 ± 1.7; del Nido: ∆Ct 8.8 ± 1.5, p = 0.01) and the brain stem (HTK: ∆Ct 5.7 ± 1.5; del Nido: ∆Ct 7.5 ± 1.6, p = 0.02) of the HTK group. In conclusion, we showed comparability of HTK and del Nido for cerebral inflammation except for IL-1β expression. Based on our study results, we conclude that del Nido cardioplegia is a suitable and safe alternative to the conventional HTK solution.