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Mesenchymal stem cell‐derived conditioned medium (MSC‐CM) improves cardiac function after myocardial infarction; however, this cardioprotective effect is moderate and transient. Lipopolysaccharide (LPS) pretreatment partially improves MSC‐CM‐mediated cardioprotective effects owing to the presence of paracrine factors. However, the mechanism underlying these improved effects remains unknown. To study the effect of LPS‐pretreated MSC‐CM on hypoxia/reoxygenation (H/R)‐induced injury, MSCs were treated with or without LPS (400 ng/mL) for 48 h, and the supernatant was collected (MSC‐CM). Subsequently, H9c2 cells were co‐cultured with Nor‐CM (CM derived from LPS‐untreated MSCs) and LPS‐CM (CM derived from LPS‐pretreated MSCs) for 24 h and subjected to H/R. MSC‐CM inhibited the progression of H/R‐induced injury in H9c2 cells, and this protective effect was enhanced via LPS pretreatment as evidenced by the improved apoptosis assessment index (i.e. caspase‐3 and B‐cell lymphoma‐2 [Bcl‐2] expression) and decreased levels of lactic dehydrogenase (LDH) and cardiac troponin (cTn). In addition, the results of haematoxylin–eosin staining (H&E), transmission electron microscopy (TEM) and TdT‐mediated dUTP nick‐end labelling (TUNEL) validated that MSC‐CM inhibited H/R‐induced injury in H9c2 cardiomyocytes. LPS pretreatment downregulated the expression of high mobility group box‐1 (HMGB1) and BTB and CNC homology‐1 (Bach1) proteins in MSCs but upregulated the expression of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF) and insulin‐like growth factor (IGF). HMGB1 knockdown (MSC/siHMGB1‐CM) significantly decreased the expression of Bach1 and increased the expression of VEGF, HGF and IGF. Bach1 knockdown (MSC/siBach1‐CM) did not alter the production of HMGB1 but increased the expression of VEGF and IGF. LPS pretreatment did not alter the expression of the paracrine factors VEGF and HGF in the MSC/siHMGB1 group but increased their expression in the MSC/siBach1 group. The myocyte anti‐apoptotic effects of MSCs/siBach1‐CM were similar to those of untreated MSCs, which were not enhanced by LPS. LPS‐pretreated MSC‐CM protects H9c2 cells against H/R‐induced injury partly through the HMGB1/Bach1 signalling pathway. [ABSTRACT FROM AUTHOR]