Since its emergence as a cardiovascular epidemic in 1997, heart failure (HF) continues to be a significant challenge globally both economically and in clinical practice. As a consequence of the lack of effective treatments available, significant efforts have been devoted with the aim of identifying novel therapeutic strategies to treat HF. Loss of Mitogen-activated Protein Kinase Kinase 7 (MKK7) in the myocardium has previously been shown to underpin ventricular hypertrophy and HF progression. We demonstrated that adeno-associated virus 9 (AAV9) cardiac-specific overexpression of MKK7 therapeutically impeded cardiac dysfunction, interstitial fibrosis and cardiomyocytes apoptosis following 5-weeks pressure overload-induced HF. It was found that this was achieved, at least partly, by ameliorating Endoplasmic Reticulum (ER) stress. Mechanistically, in vivo and in vitro analysis revealed that although overexpression of MKK7 had no effect on PERK-ATF4 or ATF6 signalling pathways, the IRE1-XBP1 signalling pathway was preserved and a hindered increase in CHOP expression was observed. In conclusion, overexpression of MKK7 holds therapeutic potential in mitigating the pathological cardiac changes associated with HF progression.