Approximately 85,000 adolescent and young adults (AYAs; age 15–39) are diagnosed with cancer in the United States annually. Experiencing a cancer diagnosis as an AYA can substantially impact social connections and social health. This paper describes the design and protocol of an observational study to prospectively assess social health and its association with physical activity and quality of life among AYAs after a cancer diagnosis. The study uses a longitudinal observational design to prospectively explore the relationships between social health and activity behaviors (physical activity and sedentary time) at four clinically significant timepoints over the course of 12 months among AYAs newly diagnosed with cancer. Patients are recruited at three hospitals and surveyed at each time period. Multiple dimensions of social health are assessed including social support, social roles, loneliness, social anxiety, and social networks. A wrist accelerometer is worn for one week at each assessment period. Change in social network structures will be analyzed using egocentric social network analysis. Structural equation models will be fitted to analyze the relationship between social constructs and physical activity. Findings from this study will address gaps in our understanding of the impact of a cancer diagnosis on multiple dimensions of social health for AYAs and the potential role social factors play in physical activity and quality of life. Understanding these processes will inform age-tailored interventions to improve health and quality of life outcomes for this at-risk population.