How co-morbid mood and metabolic disturbances interact to promote ischemic heart disease development and decrease myocardial ischaemic tolerance is largely unknown. This study examined whether chronic low-level stress and a Western diet (WD) synergistically reduce myocardial infarct tolerance and responsiveness to established cardiac conditioning stimuli. Sixty-four male C57BL6/J mice were exposed to a control diet (CD) (14% fat, 59% carbohydrates, 19% protein) or a WD (32%/57%/11%) for 16 weeks. Methods: Mice were randomised into four groups: CD, WD, CD + restraint stress (RS), and WD + RS. RS groups were exposed to low-level chronic stress during the final 14 days of feeding. Hearts from these animals were subjected to ischemic pre-conditioning (IPC) or ischemia/reperfusion (I/R). Results: Body weight was increased by the WD (p<0.0001) while RS decreased body weight in both WD and CD groups. Food intake was greater in the WD-fed mice (p<0.0078) until the introduction of the RS protocol which resulted in a significant reduction in WD consumption. The WD increased fasting insulin (p<0.0001 vs. CD) and glucose (p<0.0001 vs. CD). Sucrose preference test results suggest that the WD may have induced anhedonia (p<0.0001). Myocardial ischemic tolerance was improved by IPC in both the CD and WD hearts but not RS groups, irrespective of diet. IPC did not reduce myocardial cell death (LDH release) after I/R in any of the groups. Cell death (LDH release) was reduced by IPC in the CD group when compared with the WD + RS hearts, suggesting that a WD combined with stress may act synergistically to reduce the heart’s response to cardiac pre-conditioning. Conclusions: A WD and low-level stress promotes metabolic dysregulation and myocardial cell death during I/R and makes the heart unresponsive to IPC. However, co-morbid WD and stress do not worsen myocardial infarct tolerance and I/R injury.