The objective of the present study was to investigate the impact of myeloid Src homology region 2‑containing protein tyrosine phosphatase 2 (SHP2) on myocardial ischemia reperfusion (MI/R) injury and the underlying mechanism. Bioinformatics was used to analyze genes specifically associated with MI/R. In addition, myeloid‑specific SHP2 knockout mice and wild‑type mice were subjected to MI/R or sham surgery. Echocardiography and Masson's staining were used to observe the myocardial function and infarct area of the mice. In addition, double immunofluorescence staining was used to detect the relative fluorescence intensity of SHP2 and bromodomain‑containing protein 4 (BRD4) in bone marrow‑derived macrophages (BMMs) from the mice. Western blot analysis was conducted to determine the expression levels of SHP2, BRD4, spleen tyrosine kinase (SYK), stimulator of interferon genes (STING), NADPH oxidase 4 (NOX4), NLR family pyrin domain containing 3 (NLRP3), IL‑1β and gasdermin D (GSDMD) in BMMs and mouse myocardial cells co‑cultured with the BMMs. In addition, flow cytometry was employed to assess myocardial cell apoptosis. Bioinformatics analysis revealed the downregulated expression of SHP2 and upregulated expression of BRD4 and SYK in mice with MI/R. The deletion of myeloid SHP2 aggravated MI/R injury, impaired cardiac function and increased the infarct area in mice. In addition, myeloid SHP2 deletion in BMMs promoted the expression of BRD4, SYK, STING, NOX4 and NLRP3 in BMMs, and the expression of IL‑1β and GSDMD in mouse myocardial cells co‑cultured with the BMMs. In addition, the deletion of myeloid SHP2 promoted cardiomyocyte apoptosis. These results indicate that myeloid SHP2 inhibits MI/R injury by regulating BRD4/SYK/STING/NOX4/NLRP3 signaling in BMMs.