Cardiovascular diseases pose a major health problem, representing a significant threat to the global population due to their high mortality rates. According to the World Health Organization (WHO), cardiovascular diseases were the leading cause of death worldwide in 2021. This condition is caused by the accumulation of fatty deposits in the arteries, known as atherosclerosis, which obstructs blood flow and increases the risk of heart attacks. This study aimed to evaluate the relationship between the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) and the severity of acute coronary syndrome at Adam Malik General Hospital. This study was an analytical study with a retrospective design, utilizing secondary data obtained from patients’ medical records over a specific period. Patient data were collected from January 2023 to December 2024 from patients hospitalized at Adam Malik Hospital. Sampling was conducted using a total sampling technique, including all 208 patients who met the inclusion criteria during the study period. The collected data were then analyzed using the Kolmogorov–Smirnov test to assess the normality of data distribution. Among 208 patients, 76% were male, with a mean age of 62.2 years (range: 36–81). Most patients had low SYNTAX II scores (74%). The mean NLR and PLR values were 3.58 and 134.35, respectively. A significant positive correlation was observed between NLR and SYNTAX II score (r = 0.284; p < 0.001) and between PLR and SYNTAX II score (r = 0.143; p = 0.039). This study demonstrated a significant positive correlation between the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) and the severity of acute coronary syndrome based on the SYNTAX II score. NLR showed a stronger correlation than PLR, highlighting its superior potential as an inflammatory biomarker for assessing disease severity in patients with acute coronary syndrome.