Aim <p>This study aimed to compare the clinical characteristics and outcomes of patients hospitalized with acute coronary syndrome (ACS) before and after the COVID-19 pandemic, with particular emphasis on COVID-19 infection history and vaccination status.</p> Materials and methods <p>This retrospective, single-center study included patients admitted to the emergency department (ED) and hospitalized with a diagnosis of ACS during the pre-pandemic period (2018–2019) and the post-pandemic period (2023–2024). Patients were compared in terms of age, sex, ACS subtype, comorbidities, major adverse cardiovascular events (MACE), length of hospital stay, and mortality. In the post-pandemic cohort, subgroup analyses were performed based on COVID-19 infection status and vaccination status.</p> Results <p>A total of 4,408 patients were included, of whom 1,164 (26.4%) were female and 3,244 (73.6%) were male, with a mean age of 59.1 ± 12.5 years. No significant differences were observed between the pre- and post-pandemic periods regarding age, sex distribution, total ACS case numbers, or MACE rates. However, a statistically significant increase in STEMI-related hospitalizations and a significant decrease in the proportion of NSTEMI cases were observed in the post-pandemic period. The length of hospital stay for coronary artery disease was significantly longer after the pandemic, whereas mortality rates did not differ significantly between periods.</p> Conclusion <p>Our findings reveal no significant correlation between COVID-19 vaccination or previous SARS-CoV-2 infection and the incidence of ACS presentations. Additionally, we observed no notable influence on clinical outcomes or medium- to long-term MACE rates among patients hospitalized with ACS in the post-pandemic period. While these findings suggest no adverse association between vaccination status and clinical outcomes among patients presenting with ACS, further large-scale, multicenter studies are needed to clarify potential long-term associations.</p>