Objective To explore the effect of isosorbide mononitrate combined with β-blocker on the serum levels of H-FABP and GDF-15 in patients with acute myocardial infarction. Methods A total of 108 patients with acute myocardial infarction treated in Yima People's Hospital of Henan Province from February 2019 to February 2020 were selected and divided into β-blocker group and combined treatment group according to odd-even grouping method, with 54 cases in each group. The β-blocker group was treated with β-blockers, and the combination group received isosorbide mononitrate on its basis. The levels of LVEF, LVEDD, LVPFR, CK, ET-1, NT-proBNP, sICAM-1, IL-6, hs-CRP, GDF-15, and H-FABP were measured. The occurrence of adverse reactions between the two groups was observed and compared. Results Compared with the β-blocker group, the combination group had higher level of LVEF, LVPFR, LVEDD, inflammatory factor H-FABP, GDF-15 (P<0.05); the total adverse effects in the combined treatment group were higher than those in the β-blocker group (P>0.05). Conclusion Isosorbide mononitrate combined with β-blockers can effectively improve the clinical symptoms of patients with acute myocardial infarction, promote the return of heart function to normal, and reduce the levels of myocardial infarction markers. The mechanism may be related to the reduction of H-FABP and GDF-15 levels.