Knee osteoarthritis (OA) is the most common form of arthritis, which is a leading cause of disability. Although no cure exists for knee OA, physical activity has been shown to improve functionality, which can improve an individual's health-related quality of life (HR-QOL). However, racial disparities exist in participating in physical activity, which can result in Black people with knee OA experiencing lower HR-QOL compared with their White counterparts. The purpose of this study was to investigate disparities of physical activity and related determinants, specifically pain and depression, and how these constructs explain why Black people with knee OA experience low HR-QOL. Data were from the Osteoarthritis Initiative, a multicenter longitudinal study that collected data from people with knee OA. The study used a serial mediation model to test whether a change in scores for pain, depression, and physical activity over 96 months mediated the effects between race and HR-QOL. Analysis of variance models found Black race to be associated with high pain, depression, and lower physical activity and HR-QOL at baseline and month 96. The findings supported the prospective multi-mediation model, which found pain, depression, and physical activity to mediate between race and HR-QOL (β = -0.11, SE = 0.047; 95% CI, -0.203 to -0.016). Disparities in pain, depression, and physical activity could explain why Black people with knee OA experience lower HR-QOL compared with their White counterparts. Future interventions should address sources of pain and depression disparities by improving health care delivery. Additionally, designing race- and culture-appropriate community physical activity programs would help to achieve physical activity equity.