Objective: This study aims to investigate the value of interleukin 6 (IL-6) and high-mobility group box 1 (HMGB1) in predicting major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI) in patients with acute coronary syndrome (ACS). Methods: Patients with ACS who were treated in our hospital from October 2022 to October 2023 were divided into MACE and no-MACE groups according to the occurrence of MACE after PCI. The baseline data and IL-6 and HMGB1 levels in the two groups were observed, and the influencing factors of MACE in patients with ACS after PCI were evaluated with a logistic regression test. The receiver operator characteristic curve (ROC) values of IL-6 and HMGB1 in the prediction of MACE after PCI in patients with ACS were calculated. Results: No significant differences in age, sex, body mass index (BMI), and other general data were found between the groups. Compared with the patients in the no-MACE group, the patients in the MACE group had a history of smoking (p = 0.011), hypertension (p < 0.001), diabetes (p < 0.001), more coronary lesions (p = 0.013), longer coronary lesions (p = 0.006), higher preoperative Gensini score (p < 0.001), and lower left ventricular ejection fractions (LVEF) (p < 0.001). The levels of IL-6 and HMGB1 in the MACE group were significantly higher than those in the no-MACE group. Coronary lesion length, Gensini score, LVEF, IL-6, and HMGB1 had good predictive value for MACE after PCI. The area under the curve (AUC) scores were 0.683, 0.941, 0.816, 0.878, and 0.737. The sensitivity was 53.13%, 81.25%, 84.37%, 78.12%, and 53.13%, and the specificity was 87.50%, 93.18%, 63.64%, 86.36%, and 86.36%, respectively. Analysis of IL-6 and HMGB1 levels showed that the AUC was 0.922, the sensitivity was 90.62%, the specificity was 82.95%, and the 95% confidence interval (CI) was (0.858–0.963; p < 0.05). Conclusion: IL-6 and HMGB1 have good predictive value for MACE after PCI for patients with ACS and can be used as clinical evaluation indexes.