In recent years, hypertension has emerged as the leading risk factor for disability-adjusted life years (DALYs). This study examined the relationship between quality of life, depression, and hypertension among hospitalized patients in Afghanistan. A cross-sectional survey was conducted from September 3, 2022, to February 2, 2023, in the Herat and Mazar-e-Sharif provinces (N = 2059). The study found that 65.8% of participants exhibited symptoms of depression, and 20.9% had hypertension. Multiple regression analysis revealed that moderate physical functioning, poor role-physical, higher bodily pain, poor general health, poor social functioning, lower role-emotional, and poor mental health were significant predictors of depression. Similarly, moderate quality of life, poor physical functioning, higher bodily pain, lower energy/fatigue, and depression were significant predictors of hypertension. The findings provide valuable insights for healthcare providers, policymakers, and researchers to develop targeted interventions and policies aimed at improving the well-being of individuals facing depression and hypertension. Given the high prevalence of these conditions in the Herat and Mazar-e-Sharif provinces, hospitals should prioritize regular screening for depression and provide psychological counseling for patients with hypertension.