Objective To investigate the relationship between serum galactin-3 (Gal-3) and high mobility histone 1 (HMGB1) levels and prognosis after percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI). Methods A total of 115 patients with AMI were included in this study. All patients received PCI and were followed up for half a year after treatment. Patients with and without adverse cardiovascular events were divided into MACE group (35 cases) and reference group (80 cases), respectively. Serum Gal-3, HMGB1 and cTnⅠ, CRP and other indexes were detected and compared before and after operation, and the levels of cTnⅠ, CRP, serum Gal-3 and HMGB1 were compared between the MACE group and the reference group. Receiver operating characteristic (ROC) curve was used to analyze the value of the above indexes in predicting the poor prognosis of patients with acute myocardial infarction. Results The levels of serum Gal-3 and HMGB1 after operation were higher than those before operation (P<0.05). Compared with the reference group, the indexes of cardiac function and inflammatory factors in MACE group were increased, while the indexes of left ventricular ejection fraction (LVEF) were decreased in MACE group (all P<0.05). Serum Gal-3 and HMGB1 levels in MACE group were higher than those in reference group (P<0.05). The AUC values of serum Gal-3 and HMGB1 indexes for predicting poor prognosis in patients with acute myocardial infarction were 0.723 and 0.708, respectively, and the sensitivity were 61.40% and 54.55%, respectively, while the AUC values of combined prediction were 0.791 and the sensitivity was 82.43%, both of which were higher than the single detection of each indicator. Conclusion The levels of serum Gal-3 and HMGB1 indexes in patients with acute myocardial infarction showed an abnormal increase trend, and the combined detection of these indexes is of high clinical value in predicting the occurrence of MACE in patients with acute myocardial infarction.