Introduction: As with obesity, early life stress (ELS) increases risk for mood disorders, cardiovascular risk factors and cardiovascular disease (CVD). Consumption of a Western diet (WD) characteristically high in saturated fat, refined sugar, and energy, leads to obesity, insulin resistance, and dyslipidaemia. Similarly, ELS has been associated with the same cardiometabolic risk factors, although a causal relationship between ELS and these risk factors remains unclear. While it is well established that consuming a WD can negatively affect cardiac ischaemia/reperfusion injury, whether ELS (alone or combined with a WD) can exacerbate ischaemia/reperfusion injury remains unclear. We assessed the influence of ELS and a WD on behaviour, cardiometabolic-risk factors, and post-ischaemic cardiac outcomes. Methods: Fifty-six new-born male C57BL/6J mice were randomly divided into two groups; exposed to no stress (CON) or to 180 min/day of maternal separation and weaned early at postnatal day 17 (MSEW). At 8 weeks, groups were randomly subdivided and assigned to either a standard rodent chow (percentage of total calorie content contributed by 23% protein; 65% carbohydrates; 10% unsaturated fat; 2% saturated fat) or a WD (16% protein; 66% carbohydrates; 20% unsaturated fat; 17% saturated fat) for the next 16 weeks. The four groups were: CON (n=14); MSEW (n=15); WD (n=19); and MSEW+WD (n=19). At weeks 7, 15, and 23 fasted blood glucose was assessed, serum collected for subsequent quantification of insulin, triglyceride (TG) and corticosterone concentrations. Open field and elevated plus maze tests were also performed at weeks 7, 15, and 23 to assess behavioural change. At 24 weeks, Langendorff heart perfusions were performed to evaluate pre- and post-ischaemic cardiac function. Results: The MSEW animals displayed hyperactive behaviour at week 7 as measured by the open field test (p<0.05), whilst WD and MSEW+WD animals displayed depressive and anxiety-like behaviours at week 23 in the open field test and elevated plus maze, respectively (all p<0.05). MSEW animals were heavier with increased fasted serum TGs (p<0.05), which was not sustained, normalising at week 15. MSEW did induce long-term hyperglycaemia (p<0.05) but there were no differences in fasted serum insulin. The WD and MSEW+WD animals exhibited increased body mass, fasted blood glucose, insulin and TG levels compared to CON (all p<0.05). However, MSEW+WD animals were heavier than WD animals from weeks 10-24, with greater baseline cardiac function at 24 weeks than CON animals (all p<0.05). MSEW rendered hearts slightly more tolerant to ischaemic insult whereas a WD decreased ischaemic tolerance, though neither change achieved statistical significance (p>0.05). Conclusions: Despite evidence of anxiety and increased cardiovascular risk factors (e.g. hyperglycaemia, insulin resistance) with MSEW, hearts from these mice tended to be more resilient, with positive effects on ischaemic tolerance. Animals on a WD also displayed depressive and anxiety-like behaviours and a worsened cardiometabolic risk profile, with a trend to decreased myocardial ischaemic tolerance. A combination of MSEW and a WD induced greater metabolic disruption than individually, with MSEW countering the adverse effects of the WD. ELS and a WD may thus promote risk of CVD, however as opposed to the WD, ELS may trigger adaptive cardiac changes rendering hearts resistant to injury.