Purpose <p>Myocardial reperfusion following ischaemia paradoxically exacerbates mitochondrial and thus cardiac dysfunction. Although various treatment strategies have been utilised to prevent irreversible myocardial injury, translation to positive clinical trial outcomes has been unsuccessful. This systematic review aimed to evaluate pharmacological interventions in animal models of ischaemia–reperfusion (I/R), with emphasis on cardiac and cell death outcomes and direct assessment of mitochondrial bioenergetics.</p> Methods <p>Search terms were entered into PubMed, Scopus, Embase and Web of Science. Screening, data extraction and quality assessment of papers were conducted according to the inclusion and exclusion criteria selected for this study. Eighteen papers from a total of 1571 studies were included. These studies investigated 15 drugs of interest in animals subjected to either in vivo or ex vivo I/R. Mitochondrial function parameters were assessed by measuring either mitochondrial respiration and/or enzyme activity, with 4 of these also assessing electron transport chain protein expression.</p> Results <p>Pharmaceuticals preserved mitochondrial respiratory capacity by directly targeting the electron transport chain complexes or indirectly via proteins involved in canonical cardioprotective pathways. This led to improved post-ischaemic cardiac function and reductions in markers of cellular injury and myocardial infarction.</p> Conclusion <p>Multi-targeted manipulation of components of mitochondrial signalling and function evidently reduces I/R injury. Quality assessment of most papers revealed an unclear risk of bias due to inadequate reporting of study parameters. Clear and consistent reporting of study outcomes, specifically mitochondrial bioenergetics across all experimental stages, is essential to enhance the translational potential of mitoprotective compounds in the clinical treatment of I/R.</p>