Calcium dobesilate (CaD) is an established vasoactive and angioprotective drug commonly used for the clinical treatment of diabetic retinopathy and chronic venous insufficiency. It has antioxidant properties and controls vascular permeability. In the current study, we explored the possible role of CaD against anxiety and cognitive dysfunction as well as against oxidative brain damage induced by D-gal treatment in mice. D-galactose (D-gal) long-term treatment in mice induces the overproduction of reactive oxygen species (ROS) and is a well-accepted experimental model of oxidative stress-linked cognitive disorders in physiological aging. CaD was administered (50 and 100 mg/kg/day p.o.) in male mice treated with D-gal (500 mg/kg/day p.o.) for six weeks. Thereafter, animals were behaviorally assessed in elevated plus-maze, Y-maze, and shuttle box tests, and brains were dissected for further biochemical analysis. Results demonstrated that bodyweight loss and cognitive impairments of D-gal-treated animals were reversed by CaD administration as evaluated by the measurement of mice performance. CaD treatment also inhibited brain oxidative stress in aging mouse by decreasing malondialdehyde (MDA) levels and increasing superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase (CAT) enzyme activities. With the animal model's limitation, our results suggest that CaD, which is already approved for clinical use and safe, could be an interesting pharmacological tool to reduce or prevent age-related behavioral and brain oxidative stress conditions. These results could open new perspectives for the clinical use of CaD in counteracting brain oxidative stress and preventing cognitive impairment in aging.