Objectives: The impact of beta-thalassemia major (β-TM) on health-related quality of life (HRQoL) in Oman is not yet known. Affected individuals suffer from a wide range of physical, mental, and social consequences due to the need for regular hospital visits for blood transfusions and complications related to iron overload. This study aimed to assess the HRQoL of adult patients with β-TM attending a single tertiary care center in Muscat, Oman, to identify factors influencing Omani patients’ QoL for improved management and counseling. Methods: A cross-sectional study was conducted among adult patients (≥ 18 years) with β-TM at Sultan Qaboos University Hospital between September and November 2022. A validated Arabic version of the self-reported 36-item short-form health survey was used to determine HRQoL. Results: A total of 78 patients with β-TM were enrolled in the study; 53.8% were male and the mean age was 26.0±0.8 years, ranging from 21–53 years. Most patients were from Al Batinah North governorate (n = 21; 26.9%) and Muscat (n = 20; 25.6%), unmarried (n = 44; 56.4%), did not have university-level education (n = 45; 57.7%), and were unemployed (n = 44; 56.4%). The HRQoL domain with the highest score was role limitations due to emotional problems (median score = 100), while general health and vitality received the lowest scores (mean scores were 60.2±15.9 and 59.1±20.5, respectively). Several variables were associated with better HRQoL in certain domains, including being married, having a high level of education, being employed, exercising regularly, and receiving family support (p 0.05). However, iron overload and having ≥ 3 β-TM-related disease complications were associated with poorer general health scores (p = 0.031 and 0.038, respectively), while a history of mental issues was associated with poorer scores in six out of eight HRQoL domains (p 0.05). Moreover, negative perceptions regarding the social impact of the disease including delayed marriage, workplace difficulties, and reduced academic achievement were associated with poorer HRQoL in various domains (p 0.05). Conclusions: Although the studied sample reported generally good QoL, several factors were found to affect HRQoL in various domains. Healthcare providers should prioritize maintaining acceptable iron overload levels in Omani patients with β-TM to help avoid the development of disease-related complications, thereby ensuring better control of their clinical conditions and consequently improving their HRQoL.