Approximately 59% of adults living with HIV experience HIV-Associated neurocognitive disorder, a collection of symptoms and cognitive deficits in various cognitive domains. As the HIV population ages, the prevalence and severity of such cognitive deficits are expected to grow. Understanding how these cognitive deficits manifest is important for nurses and health care providers. This article provides an overview of cognitive reserve and evidence of how it is compromised by HIV, aging, and individual characteristics. Within this context of cognitive reserve, the role of neuroinflammation, neurotoxicity, substance use, comorbidities, depression and anxiety, social isolation, and sedentary lifestyle is reviewed. From this, strategies used to address cognitive deficits are provided, including topics such as psychostimulants, cognitive training, multimodal lifestyle interventions, and compensation strategies. Scenarios of successful and unsuccessful cognitive aging are presented to provide a lifespan perspective of cognitive reserve. Implications for clinical practice and research are provided, as it relates to aging.