Background: Cardiovascular diseases ranked first in terms of the number of deaths in Serbia in 2019, with 52,663 deaths. One fifth of those were from ischemic heart disease (IHD), and half of IHD deaths were from acute coronary syndrome (ACS). We present the ACS mortality time trend in Serbia during a 15-year period using the latest available data, excluding the COVID-19 pandemic. Methods: The data on patients who died of ACS in the period from 2005 to 2019 were obtained from the National Statistics Office and processed at the Department of Prevention and Control of Non-communicable Diseases of the Institute of Public Health of Serbia. Number of deaths, crude mortality rates (CR) and age-standardized mortality rates (ASR-E) for the European population were analyzed. Using joinpoint analysis, the time trend in terms of annual percentage change (APC) was analyzed for the female and male population aged 0 to 85+. Age–period–cohort modeling was used to estimate age, cohort and period effects in ACS mortality between 2005 and 2019 for age groups in the range 20 to 90. Results: From 2005 to 2019 there were 90,572 deaths from ACS: 54,202 in men (59.8%), 36,370 in women (40.2%). Over the last 15 years, the number of deaths significantly declined: 46.7% in men, 49.5% in women. The annual percentage change was significant: −4.4% in men, −5.8% in women. Expressed in terms of APC, for the full period, the highest significant decrease in deaths was seen in women aged 65–69, −8.5%, followed by −7.6% for women aged 50–54 and 70–74. In men, the highest decreases were recorded in the age group 50–54, −6.7%, and the age group 55–59, −5.7%. In all districts there was significant decline in deaths in terms of APC for the full period in both genders, except in Zlatibor, Kolubara and Morava, where increases were recorded. In addition, in Bor and Toplica almost no change was observed over the full period for both genders. Conclusions: In the last 15 years, mortality from ACS in Serbia declined in both genders. The reasons are found in better diagnostic and treatment through an organized network for management of ACS patients. However, there are districts where this decline was small and insignificant or was offset in recent years by an increase in deaths. In addition, there is space for improvement in the still-high mortality rates through primary prevention, which at the moment is not organized.