Health-related quality of life (HRQoL) assessment is important for patients with functional dyspepsia. However, no studies have assessed factors associated with HRQoL reduction in such patients in an Asian population. This study aimed to determine the contribution of clinical, psychosocial, and demographic factors to HRQoL in affected patients in Indonesia. In a cross-sectional study, we recruited 124 patients in a tertiary hospital with functional dyspepsia according to Rome III criteria. HRQoL was measured using the Medical Outcomes Study Short-Form 36 (SF-36) physical component summary (PCS) and mental component summary (MCS) and compared with 2009 United States population norms. The factors investigated were age, gender, symptom severity, education level, employment status, anxiety, depression, and ethnicity. Factors associated with reduced HRQoL were identified using linear regression analysis. All domains of HRQoL except vitality were impaired in patients with functional dyspepsia. The mean PCS was 42.3 (SD = 8.4); and the mean MCS was 47.8 (SD = 10). Increasing age (p = 0.002), female gender (p = 0.006), low-to-mid education level (p = 0.015) and greater symptom severity (p < 0.001) were significantly associated with impaired PCS (R  = 0.36). Female gender (p = 0.047), greater symptom severity (p = 0.002), anxiety (p = 0.001), and depression (p = 0.002 were all significantly associated with an impaired MCS (R  = 0.41). There were no significant associations between HRQoL and with ethnic group (Javanese/non-Javanese) or employment status. There was significant HRQoL impairment in these patients with functional dyspepsia in Indonesia. Anxiety, depression, increasing age, female gender, greater symptom severity, and low-to-mid education level were significant factors associated with low HRQoL.  TRIAL REGISTRATION: ClinicalTrials.gov NCT03321383 . Registered 18 October 2017 retrospectively registered.