The COVID-19 pandemic in Thailand is part of the global pandemic of coronavirus disease 2019 caused by SARS-coronavirus 2 (SARS-CoV-2). Because of the high population density, Bangkok Metropolitan Region was the one of the major epicenters of COVID-19 epidemic in Thailand during the Delta wave in 2021. The explosive number of COVID-19 patients during that time brought the Thai government to initiate home isolation program. Methods A retrospective cohort study was conducted. All recorded COVID-19 patients in Bangkok Metropolitan Region enrolled into the home isolation program (HI) were identified from A-MED Telehealth electronic health records (EHRs) data during 1 July 2021 and 31 December 2021. Furthermore, the vital status of the enrolled patients was evaluated from the National Civil Registration database on 20 September 2022. Mortality within 28 days and associated factors were analyzed using Kaplan-Meier method and Cox proportional hazard model. Results The total number of participants was 90,861, with the 14th of August having the highest admission of 3,391 registrants. The HI care system in Bangkok Metropolitan Region during the study period consisted of two major components: standard health systems and the services under the HI crisis response task force for COVID-19 patients. In standard health systems, the operation sectors included BMA Medical Service Department hospitals, public health service centers, and private clinics, whereas the services under the HI crisis response task force included Fammed CoCare (Tangerine Clinic) supported by the Royal College of Family Physicians of Thailand and the Thai Red Cross Society. Fammed CoCare was accountable for up to 50% of COVID-19 patients in July, the first month of HI protocol implementation. The average age was 37.28±18.96 years old. Almost half of the participants were men, and 55.70% were covered under the universal coverage scheme. Non-Thai was included in the protocol 5.48%. Obesity was (body mass index (BMI) ≥30.00 kg/m2) 14.12%. The percentages of healthcare centers in charge of the HI program (public health service centers, private clinics, Fammed CoCare (tangerine clinic)) were 38.76%, 24.18%, 20.86% respectively. Asymptomatic, mildly symptomatic, urgent symptoms, death, resolution, and urgent administration (42.80%, 29.50%, 1.20%, 0.01%, 0.70%, and 9.30%, respectively) are initial symptoms. Andrographis paniculate, Favipiravir, and oral steroid are among the medications prescribed (8.70%, 23.00%, and 0.53%, respectively). During a follow-up period 988.54 person-years, 1,349 participants died. 50% and 8% of the death was happened within 28 days after days of illness (DOI) and during the HI program, respectively. 20% of death was occurred at home. COVID-19 accounted for 70% of all causes of mortality, while non-expected natural causes accounted for 55.40% of all other causes of death. Suicide was the leading cause of death within 8 weeks of DOI. Conclusion The unprecedented COVID-19 pandemic outbreak needs adaptable systems capable of responding in timely manner to patient management. Standard health systems, particularly in the early stages, should coordinate with the services under the HI crisis response task force for COVID-19 patients, which has the flexibility to assemble multidisciplinary teams. The many lessons learnt from the current COVID-19 problem were used to guide the future paths of outbreak management systems in this situation.