As life expectancy increases, frailty and cognitive impairment have become major factors influencing healthy aging in elderly individuals. Frailty is a complicated clinical condition characterized by decreased physiological reserve and multisystem abnormalities. Cognitive frailty is a subtype of frailty that has aroused widespread concern among the scientific community and public health organizations. We herein review the pathogenesis of cognitive frailty, such as chronic inflammatory response, immunological hypofunction, imbalanced oxidative stress, reduced regenerative function, endocrine dysfunction, and energy metabolism disorder. Although existing interventions show some therapeutic effects, they do not meet the current clinical needs. To date, studies using stem cell technology for treating age-related diseases have achieved remarkable success. This suggests the possibility of applying stem cell treatment to cognitive frailty. We analyzed stem cell-based strategies for targeting anti-inflammation, antioxidation, regeneration, and immunoregulation using mesenchymal stem cells, as well as potential therapeutic targets for cognitive frailty. Based on this investigation, we propose a highly effective and low-cost stem cell-based replacement strategy. However, there is a lack of comprehensive research on the prospect of stem cell transplantation for improving cognitive frailty. In this review, we aim to provide the scientific background and a theoretical basis for testing cell therapy in future research.