Background Hepatic encephalopathy has a negative effect on patient health-related quality of life (HRQOL). Zinc supplementation has been effective with regard to altered nitrogen metabolism. Aim To investigate the effectiveness of oral zinc supplementation on hepatic encephalopathy and HRQOL. Methods Seventy-nine cirrhotic patients with hepatic encephalopathy were randomized to receive 225 mg of polaprezinc in addition to standard therapies of a protein-restricted diet including branched-chain amino acid and lactulose, or to continue only standard therapies for 6 months. The change of HRQOL by Short Form-36, hepatic encephalopathy grade, laboratory parameters, and neuropsychological (NP) tests were compared at baseline and at 6 months. We also evaluated via multivariate analysis whether zinc supplementation and clinical variables correlated with the changes in physical component scale (PCS) and mental component scale (MCS) between the two visits. Results Zinc supplementation significantly improved the PCS (P = 0.04), but not the MCS (P = 0.95). Zinc supplementation significantly decreased hepatic encephalopathy grade and blood ammonia levels (P = 0.03 and P = 0.01), and improved Child-Pugh score and NP tests compared with standard therapy (P = 0.04 and P = 0.02). In multivariate analysis, zinc supplementation was significantly associated with improvement in PCS (P = 0.03), whereas it was not significantly associated with change in MCS (P = 0.98). Conclusion Zinc supplementation is effective in hepatic encephalopathy and consequently improves patients HRQOL.