Serum ammonia testing in hepatic encephalopathy (HE) has been long debated in the field of hepatology. Although central to the pathophysiology of HE, serum ammonia testing is fraught with complexities that can lead to challenges in laboratory collection and interpretation. Although there is some disagreement across guideline organizations regarding routine testing of ammonia in HE, all acknowledge that normal values, although possible in HE, may warrant reconsideration of the diagnosis. In this study, we propose a nuanced approach to ammonia testing in HE. Serum ammonia testing provides little additional benefit in clinical scenarios with a high or low pretest probability for HE. However, if the pretest probability for HE is uncertain, a low ammonia level may reduce the posttest probability of HE. In this scenario, other etiologies of altered mental status should be explored. Future research should focus on developing a standardized approach to serum ammonia collection, processing, and interpretation.