Perfusion asymmetries have been associated with vascular pathology. Physical activity is a component of vascular health. Here, we investigate the impact of a thirty-day regular home-based physical activity program in older individuals with multiple age-related comorbidities. Eleven participants of both sexes were included. Skin perfusion was assessed in both feet by laser Doppler flowmetry (LDF, for deeper perfusion) and polarized light spectroscopy (PSp, for superficial perfusion). At baseline, participants had significant perfusion differences between right and left feet (p = 0.005 with LDF; p = 0.028 with PSp), which disappeared with activity and reappeared in recovery. After 30 days, both feet showed significant perfusion increases as assessed with LDF (p = 0.005) compared to D0. At this point, the perfusion asymmetry observed at D0 was no longer present. However, the superficial perfusion asymmetry assessed by PSp persisted at D30 (p = 0.028). Data show that regular physical activity positively altered the lower limb perfusion pattern. Systolic pressure and mean arterial pressure were also significantly reduced at D30. These impacts seem to be directly related to the physical activity program introduced in the day-by-day routines of these participants. These also encourage further research on the role of symmetry-asymmetry in prevention, treatment, and rehabilitation in vascular medicine.