This work was conducted to assess the effects of quercetin and exercise on depressive-like behaviour. Fifty Albino rats were categorized into five groups, Control group (saline + vehicle) for 10 days, Depression group: lipopolysaccharide (LPS) was intraperitoneally (IP) injected (0.5 mg/kg/day) for 10 days, Depression group treated by quercetin: LPS was IP injected (0.5 mg/kg/ day) then intragastric injection of quercetin (40 mg/kg/day) for another 10 days, Depression group treated by exercise: LPS was IP injected (0.5 mg/kg/day) then rats was treated with treadmill exercise for another 10 days, and Depression group treated by quercetin and exercise: LPS was injected, then quercetin was administered in addition to treadmill exercise. At the end of the experiment, behavioural changes were examined. H2O2, MDA, GSH, IL-1β, TNF-α, caspase-3, and brain neurotransmitters such as serotonin and BDNF were assessed, and PINK1 and Parkin mRNA levels were assessed. A histopathological assessment of the hippocampus was performed. LPS elicited behavioural impairments and substantially augmented H2O2, MDA, IL-1β, TNF-α, caspase-3, PINK1 and Parkin levels, with considerably reduced serotonin, BDNF and GSH levels. Meantime, quercetin and exercise effectively suppressed LPS-induced cognitive impairment and attenuated H2O2, MDA, IL-1β, TNF-α, caspase-3, PINK1 and Parkin levels, and enhanced serotonin, BDNF and glutathione levels, with greater impact reported in the combination group. Our findings suggest that quercetin combined with treadmill exercise can relieve LPS-induced depression-related behaviour via modulation of redox status, inflammation, and mitophagy.