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Background: The epidemiological transition, touted as occurring in Ghana, requires research that tracks the changing patterns of diseases in order to capture the trend and improve healthcare delivery. This study examines national trends in mortality rate and cause of death at health facilities in Ghana between 2014 and 2018. Methods: Institutional mortality data and cause of death from 2014–2018 were sourced from the Ghana Health Service's District Health Information Management System. The latter collates healthcare service data routinely from government and non-governmental health institutions in Ghana yearly. The institutional mortality rate was estimated using guidelines from the Ghana Health Service. Percent change in mortality was examined for 2014 and 2018. In addition, cause of death data were available for 2017 and 2018. The World Health Organisation's 11th International Classification for Diseases (ICD-11) was used to group the cause of death. Results: Institutional mortality decreased by 7% nationally over the study period. However, four out of ten regions (Greater Accra, Volta, Upper East, and Upper West) recorded increases in institutional mortality. The Upper East (17%) and Volta regions (13%) recorded the highest increase. Chronic non-communicable diseases (NCDs) were the leading cause of death in 2017 (25%) and 2018 (20%). This was followed by certain infectious and parasitic diseases (15% for both years) and respiratory infections (10% in 2017 and 13% in 2018). Among the NCDs, hypertension was the leading cause of death with 2,243 and 2,472 cases in 2017 and 2018. Other (non-ischemic) heart diseases and diabetes were the second and third leading NCDs. Septicaemia, tuberculosis and pneumonia were the predominant infectious diseases. Regional variations existed in the cause of death. NCDs showed more urban-region bias while infectious diseases presented more rural-region bias. Conclusions: This study examined national trends in mortality rate and cause of death at health facilities in Ghana. Ghana recorded a decrease in institutional mortality throughout the study. NCDs and infections were the leading causes of death, giving a double-burden of diseases. There is a need to enhance efforts towards healthcare and health promotion programmes for NCDs and infectious diseases at facility and community levels as outlined in the 2020 National Health Policy of Ghana. [ABSTRACT FROM AUTHOR]