Co-morbidities and multi-morbidity are emerging as the new norm in modern societies. Obesogenic diets and psychosocial stressors may be important in this trend, although how they interact is controversial: palatable diets may ameliorate behavioural effects of stress, whereas obesity may exaggerate metabolic disruption. We investigated the interactive effects of a hypercaloric Western diet (WD) and chronic stress on brain mitochondrial activity. Male C57Bl/6 mice received a control or WD (32%/57%/11% calories from fat/carbohydrates/protein) for 16 weeks, with chronic restraint stress (CRS; 1 hr restraint/day) implemented in sub-sets throughout the final 2 weeks. Behaviour was assessed via sucrose preference and open-field tests. Frontal cortex (FC), hippocampus, hypothalamus, and nucleus accumbens (NAc) were surgically isolated from the left hemisphere, homogenised in Mir05 respiration media, lysate normalised to 1 mg/mL and ~2.2 mL loaded into an Oroboros 02k-oxygraph to measure mitochondrial respiration. The WD increased body weight, an effect amplified when combined with CRS, while CRS alone had no effect. Cerebral mitochondrial activity was impaired by stress (p<0.005), including reduced maximal Complex I and leak respiration together with cytochrome c respiration, the latter reflecting potential disruption of mitochondrial membrane integrity. Mitochondrial effects were most prominent in FC, followed by hippocampus/NAc, and hypothalamus. A WD did not independently modify respiratory function across the 4 brain regions. However, the WD ameliorated in part stress-dependent respiratory dysfunction, although peak Complex I respiration was still reduced compared to a WD alone (p<0.05). Respiratory changes were mirrored by hedonic behaviour: chronic stress reduced sucrose preference while WD feeding countered anhedonia. Summarising these observations: i) cortical respiratory function is particularly sensitive to chronic stress, followed by hippocampus, hypothalamus and NAc; ii) a WD protects against cerebral mitochondrial dysfunction; and iii) these mitochondrial changes may contribute to both stress-dependent anhedonia and behavioural benefits of a WD in chronically stressed mice.