Aim Hyperglycaemia is an important risk factor for acute myocardial infarction. It can lead to increased induction of non‐oxidative glucose pathways (NOGPs) – polyol and hexosamine biosynthetic pathways, advanced glycation end products and protein kinase C – that may contribute to cardiovascular diseases onset. However, the precise underlying mechanisms remain poorly understood. Here we hypothesized that acute hyperglycaemia increases myocardial oxidative stress and NOGP activation resulting in cardiac dysfunction during ischaemia–reperfusion and that inhibition of, and/or shunting flux away from NOGPs [by benfotiamine (BFT) treatment], leads to cardioprotection. Methods We employed several experimental systems: (i) Isolated rat hearts were perfused ex vivo with Krebs‐Henseleit buffer containing 33 mm glucose vs. controls (11 mm glucose) ± global ischaemia and reperfusion ± BFT (first 20 min of reperfusion); (ii) Infarct size determination as per the ischaemic protocol, but with regional ischaemia and reperfusion ± BFT treatment; in separate experiments, NOGP inhibitors were also employed for (i) and (ii); and (iii) In vivo coronary ligations performed on streptozotocin‐treated rats ± BFT treatment (early reperfusion). Results Acute hyperglycaemia generated myocardial oxidative stress, NOGP activation and apoptosis, but caused no impairment of cardiac function during pre‐ischaemia, thereby priming hearts for later damage. Following ischaemia–reperfusion (under hyperglycaemic conditions), such effects were exacerbated together with cardiac contractile dysfunction. Moreover, inhibition of respective NOGPs and shunting away by BFT treatment (in part) improved cardiac function during ischaemia–reperfusion. Conclusion Coordinate NOGP activation in response to acute hyperglycaemia results in contractile dysfunction during ischaemia–reperfusion, allowing for the development of novel cardioprotective agents.