This study aims to determine the effect of Lipoxin (LX)A4 on myocardial ischemia reperfusion injury (MIRI) in rats and the related molecular mechanisms. Male SD rats were divided into six groups. The sham operation groups (groups C1, C2) were injected with 2 ml/kg normal saline before and after coronary artery threading, respectively. The MIRI group (groups I/R1, I/R2) were injected with normal saline before and after MIRI, respectively. The LXA4 groups (groups LX1, LX2) were injected with LXA4 before and after MIRI treatment, respectively. The hematoxylin-eosin staining and ultrastructural changes of cardiac muscle were observed. The serum levels of interleukin (IL)-1β, IL-6, IL-10, tumor necrosis factor (TNF) α and cardiac troponin I (cTnI) were measured before open-chest operation and at the end of the experiment. The mRNA and protein levels of GRP-78 and caspase-12 were determined in each group. The myocardial cell apoptosis, myeloperoxidase (MPO), superoxide dismutase (SOD), and malondialdehyde (MDA) contents were detected. The mRNA and protein levels of GRP-78 and caspase-12, the apoptosis, the serum IL-1β, IL-6, IL-10, TNF-α, and cTnI concentrations, MPO, SOD, MDA contents were significantly increased in groups I/R1, I/R2, LX1, and LX2 compared with those in groups C1 and C2 (P < 0.05). The mRNA and protein expression levels of GRP-78 and caspase-12 in groups LX1 and LX2 were lower than those in groups I/R1 and I/R2. Compared with group I/R1 and I/R2, the myocardial neutrophil infiltration and ultrastructure damage were significantly less in groups LX1 and LX2. GRP-78 and IL-10 are expressed both extracellularly and intracellularly, but are mainly expressed in the cytoplasms. In the absence of MIRI, LXA4 has no detectable effect on GRP-78 and caspase-12 expression. Before and after MIRI, application of LXA4 significantly inhibits neutrophil activation, and attenuates myocardial inflammatory injury and oxidative stress. LXA4 downregulates the mRNA and protein expression of GRP-78 and caspase-12. LXA4 could play a role in myocardial protection via a mechanism related to downregulation of GRP-78 and caspase-12, and inhibition of apoptosis.