The relationship between ethnicity, obesity and health-related quality of life outcomes in a multi-ethnic population remains poorly understood. We aim to investigate the relationship between ethnicity, body mass index (BMI), obesity-associated diseases, as well as determinants of quality of life (QoL) in Southeast Asian patients with obesity. We aim to develop and validate a simple objective score to identify patients with obesity at high risk for major depression. Associations between ethnicity, obesity-associated diseases, BMI and determinants of QoL (Patient Health Questionnaire-9 and 36-Item Short Form Survey) were analysed using multivariate logistic regression in a prospective cohort of 1501 patients with obesity. Multivariate regression and receiver operating characteristics curves were used to develop and validate a novel scoring system to identify patients at risk of major depression. Patients of Chinese, Malay and Indian ethnicity had increased risk of hypertension (odds ratio [OR]: 1.51 [95% confidence interval [CI]: 1.19-1.92, p < .001]), BMI Class 4 (OR: 17.89 [95% CI: 9.53-33.60, p < .001]) and major depression (OR: 1.71 [95% CI: 1.23-2.39, p = .002]), respectively. Factors associated with major depression (gender, ethnicity, age, obstructive sleep apnoea, Physical Component Score and Mental Component Score scores) were used to create and validate a novel scoring system with an area under curve of 0.812 (95% CI: 0.787-0.837). A cutoff of 4 of 7 points was identified with a sensitivity of 70%, specificity of 81%, positive predictive of 53% and negative predictive value of 90%. The prevalence of metabolic complications from obesity significantly varies with ethnicity. We developed a novel and simple scoring tool combining objective demographic and patient-reported outcomes to screen and triage patients at risk of major depression.