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In recent decades, hypertension has become the foremost risk factor for disability-adjusted life years (DALYs). The present study investigated the relationship between quality of life, depression, and hypertension among hospitalized patients in Afghanistan. A cross-sectional survey was administered from September 3, 2022, to February 2, 2023, in the Herat and Mazar-e-Sharif provinces of Afghanistan (N = 2059). The prevalence of depression symptoms was 65.8%, and hypertension was 20.9%. Multiple regression analysis indicated that moderate physical functioning, poor role-physical, higher bodily pain, poor general health, poor social functioning, lower role-emotional, and poor mental health significantly predicted depression. Multiple regression analysis indicated that moderate quality of life, poor physical functioning, higher bodily pain, lower energy/fatigue, and depression significantly predicted hypertension. The findings of the present study offer valuable insights for healthcare providers, policymakers, and researchers in developing targeted interventions and policies to enhance the well-being of individuals facing the challenges of depression and hypertension. The prevalence of hypertension and depression was high among patients in the Herat and Mazar-e-Sharif provinces of Afghanistan. Patients with hypertension had poor mental and physical quality of life. Hospitals should therefore implement regular screening for depression and offer psychological counseling for vulnerable patients with hypertension., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)