Acute coronary syndrome (ACS) is a comprehensive disease known as acute myocardial ischemia resulting from coronary artery plaque disruption followed by thrombosis-induced severe coronary artery stenosis and occlusions, resulting in unstable anginas (UAs), acute myocardial infarctions (AMIs) or sudden cardiac deaths. The instant study was designed to detect the level of serum markers in acute coronary syndrome with COVID-19 infection patients in Baghdad city. In the current cross-sectional study, one hundred and fifty samples were enrolled, the current study was divided into three groups 50 patients with ACS and 50 ACS with COVID-19 infection patients, while 50 samples as healthy controls, with gender and age matched individuals were included in the current study. Levels of serum IL-35 & myoglobin have been determined by ELISA technique also serum troponin was measured by qualitative method. The mean ±SD of age and gender in (ACS and ACS with COVID-19 infected) patients was no statistically significant difference. Furthermore, serum levels of myoglobin, and cardiac-specific troponin I (cTnI) were significantly higher while IL-35 was significantly decreased, in (ACS and ACS with COVID-19 infected) patients when compared to healthy controls (P≤0.01). Also, significant variation according to (ACS and ACS with COVID-19 infected) patients at (p≤0.01). The study showed lower serum IL- 35 with high cardiac enzyme levels in ACS and ACS with COVID-19 infected patients. Therefore, The results suggest that serum IL-35 level is a potential new prognostic biomarker in ACS patients with COVID-19 infection.