Alzheimer's disease (AD) is a neurodegenerative disorder with cognitive impairment. Physical exercise has long been proven to be beneficial in the disorder. The present study was designed to examine the effect of voluntary exercise on spatial memory, imaging, and pathological abnormalities. Particular focus has been given to the role of heme oxygenase-1 (HO-1)-an important cellular cytoprotectant in preserving mental acuity-using an aging rat model of dementia. Male and female Wistar rats were segregated into six groups-namely, (i) aged sedentary (control) females (ASF, n = 8); (ii) aged sedentary (control) males (ASM, n = 8); (iii) aged running females (ARF, n = 8); (iv) aged running males (ARM, n = 8); (v) young control females (YCF, n = 8); and (vi) young control males (YCM, n = 8). Rats in the ARF and ARM groups had free access to a standardized inbuilt running wheel during the 3-month evaluation period. Spatial memory was investigated using the Morris Water Test, imaging and pathological alterations were assessed using positron emission tomography (PET) imaging and histopathological examinations (H&E, Congo red staining), respectively, and HO-1 enzyme activity assays were also conducted. The outcomes suggest that voluntary physical exercise mitigates impaired spatial memory and neuropathological changes exhibited by the aging sedentary group, via elevated HO-1 activity, contributing to the antioxidant capacity in the aging brain.