A retrospective analysis of 40 extended (>2 hr) anesthetic events in eight lions (Panthera leo) and 32 tigers (Panthera tigris) was performed using a hierarchical linear growth curve model to assess the effects of anesthetic time, α-2 adrenoreceptor agonist dosages, administration of atipamezole, and biochemical parameters on rising plasma K⁺ concentrations. Hyperkalemia was first noted at a mean time of 187 min (range: 131–226 min), with time under anesthesia as a statistically significant predictor of K⁺ concentration (P < 0.0001). A significant two-way interaction between time and atipamezole administration (P = 0.0082) for rising K⁺ concentrations was demonstrated, indicating that administration of atipamezole can mitigate the rise in K⁺ concentrations. Administration of atipamezole beyond 150 min of anesthetic time was less effective in reducing K⁺ concentrations than if administered earlier. Electrocardiographic abnormalities were noted in eight animals, including three hyperkalemic individuals. Lions developed significantly greater plasma K⁺ concentrations than tigers (P = 0.0009) during anesthesia. No biochemical parameter was identified as a significant indicator of which individuals will develop hyperkalemia. Clinicians anesthetizing any large nondomestic felid should monitor electrolytes regularly during anesthetic events; consider early, partial- to full-dose reversal of α-2 agonists; and be prepared to correct potentially life-threatening electrocardiographic abnormalities resulting from hyperkalemia.