Hepatorenal syndrome (HRS) is characterized by severe renal dysfunction associated with decompensated liver cirrhosis, leading to high morbidity and mortality. This study aims to assess disparities in HRS-related mortality stratified by sex, race/ethnicity, and geographic location in the U.S. We analyzed death certificate data from the CDC WONDER database for adults aged ≥ 15 years. Age adjusted mortality rates (AAMRs) per 1,000,000 population were calculated. Joinpoint regression was used to assess annual percent change (APC) in AAMRs, with P < .05 considered significant. A total of 95,537 deaths were attributed to HRS-related mortality between 1999 and 2020. The overall AAMR declined from 1999 to 2007 (APC: −3.70; 95% CI: −5.14 to −2.84) followed by stable trend till 2018 (APC: 0.13; 95% CI: −0.74 to 0.87) and then showed a sudden increase till 2020 (APC: 9.16; 95% CI: 3.48–11.89). Men had higher AAMR than women. Non-Hispanic (NH) American Indians or Alaska Natives displayed the highest AAMR, followed by Hispanic or Latinos, NH Whites, NH Black or African Americans and NH Asian or Pacific Islander. Variations were evident across regions with the West region having highest AAMR, followed by South, Northeast and Midwest regions. Mortality was the highest in nonmetropolitan areas. HRS-related mortality in the U.S. has increased since 2018, with significant disparities across sex, race/ethnicity and region. Improving healthcare access in underserved areas is essential to addressing disparities and reducing the burden of HRS-related mortality among high-risk populations in the U.S.