Background The ability to identify indicators of poor health-related quality of life (HRQoL) is crucial for both improving clinical care and determining targets of intervention for the prevention and treatment of disease. The main objectives of this study were to assess the HRQoL profile of individuals with hypertension in Palestine, and to determine the sociodemographic and clinical characteristics associated with poor HRQoL. Methods A cross-sectional study was conducted, adopting the EuroQoL-5 Dimensions scale (EQ-5D-5 L) for the assessment of HRQoL. Patients with hypertension attending the outpatients’ clinic at Al-Makhfyah primary health care clinic and from the outpatients’ clinic at Alwatani Hospital, Nablus, Palestine, were approached for the study. The study was approved by the Institutional Review Board at An-Najah National University. Informed verbal consent was obtained from the participants before the start of the study. Findings A total of 410 patients with hypertension were enrolled from the two centres (205 patients from each centre). Of these patients, 51·95% (213 of 410) were females. The average age of the study population was 58·37 (SD 10·65) years. The mean EQ-5D-5 L index value and EQ visual analogue scale (EQ-VAS) scores were 0·80(SD 0·16) and 74·13(15·62), respectively. There was a significant positive correlation (r=0·56; p<0·001) between the EQ-5D-5L index values and the reported EQ-VAS scores. Higher EQ-5D-5L index values were significantly associated with patients who were younger than 50 years, employed, married, with income higher than US$500, who were university graduates, with a disease duration of less than 1 year, with or without one comorbid disease, and those taking 1–3 medications (Kruskal– Wallis test, p<0·05), as well as with male gender and monotherapy (Mann–Whitney test, p<0·05). Interpretation The results highlight that specific sociodemographic and disease-related characteristics of patients with hypertension, as well as treatment factors, are strongly associated with HRQoL. The study findings may be helpful in clinical practice, particularly in the early treatment of such patients, at a point at which improvement of HRQoL is still possible.