BACKGROUND The primary purpose of the current study was to determine prospective associations of accelerometer‐assessed physical activity intensity and sedentary time with health‐related quality of life (HRQOL) indicators among survivors of breast cancer. METHODS A total of 358 survivors of breast cancer wore an accelerometer for 7 days at baseline to assess different activity intensities (light, lifestyle, and moderate to vigorous) and sedentary behavior. Six months later, survivors completed online questionnaires that assessed HRQOL indicators (disease‐specific HRQOL, fatigue, depression, and anxiety) and relevant covariates. Relationships between activity and sedentary behavior quartiles and HRQOL indicator scores were examined using generalized liner models with Bonferroni multiple comparison adjustment. RESULTS After adjustment for covariates and sedentary time, each increasing lifestyle activity quartile was associated with reduced fatigue duration (P for trend, .03). Each increasing baseline moderate‐to‐vigorous physical activity (MVPA) quartile was found to be significantly associated with higher Physical Well‐Being, Functional Assessment of Cancer Therapy‐Breast (FACT‐B) total, and trial outcome index scores; fewer breast cancer‐specific concerns; and lower fatigue interference, and these differences were statistically and clinically significant between survivors in quartile 1 and quartile 4. After controlling for covariates and MVPA, relationships between sedentary time and HRQOL were mostly null with the exception of lower fatigue duration. CONCLUSIONS Objectively measured MVPA was found to be positively associated with many HRQOL indicators. Lifestyle activity was found to be only inversely associated with fatigue duration whereas sedentary time was found to be positively associated with fatigue duration. Future research is warranted to explore these relationships further. Cancer 2015;121:4044–4052. © 2015 American Cancer Society. Among survivors of breast cancer, greater objectively measured moderate‐to‐vigorous–intensity physical activity after diagnosis is prospectively associated with higher physical well‐being and overall health‐related quality of life scores, fewer breast cancer‐specific concerns, and lower fatigue interference. Increased lifestyle activity is associated with lower fatigue duration whereas increased sedentary behavior is associated with greater fatigue duration.