Following myocardial infarction (MI), reperfusion strategies ensure that blood flow is promptly restored to salvage the ischaemic myocardium. However, the sudden restoration of blood flow can inflict further damage to the ischaemic tissue, known as myocardial ischaemia/reperfusion injury (MIRI). Therapeutic strategies aimed at reducing MIRI and promoting cardiac repair remain an important clinical need. Protein-based therapies might exert benefits that limit damage and promote cardiac repair post-MI. To explore this further, we performed a systematic review of data from preclinical studies and clinical trial registries evaluating the cardioprotective effects of proteins post-MI. Medline and EMBASE were searched for preclinical studies that examined the potential cardioprotective effects of protein-based therapies to limit damage and/or mediate cardiac repair when administered after MI and/or reperfusion. Studies registered with ClinicalTrials.gov and EudraCT were also reviewed. In total, 84 studies were included in the final analysis, which included 46 different proteins. Overall, our findings support the concept that transiently applying recombinant or modified proteins after acute MI has the potential to promote lasting improvements in heart function via multiple pleiotropic mechanisms. Many of these proteins converge on a limited set of well-established signalling pathways involved in cardiac repair and remodelling after MI, with a few proteins demonstrating consistent and robust effects across multiple outcomes and models (small and large animals; reperfused and non-reperfused models). Despite this, the high potential cardioprotective benefit reported in preclinical studies has not translated into approved therapies for use in patients. Although the previous failure of protein therapies in clinical development does not invalidate the potential relevance of their downstream pathways, our research underlines the challenges in translating preclinical findings of protein-based therapies into the clinical setting. Many of these proteins converge on a limited set of well-established signalling pathways involved in cardiac repair and remodelling after MI, with a few proteins demonstrating consistent and robust effects across multiple outcomes and models (small and large animals; reperfused and non-reperfused models). Despite this, the high potential cardioprotective benefit reported in preclinical studies has not translated into approved therapies for use in patients. Although the previous failure of protein therapies in clinical development does not invalidate the potential relevance of their downstream pathways, our research underlines the challenges in translating preclinical findings of protein-based therapies into the clinical setting. Future preclinical and clinical research should examine the optimal treatment effect and fully characterise the therapeutic potential of proteins involved in post-MI remodelling.