Background The present study sought to examine the influence of physical activity on quality of life and negative mood in a sample of Black breast cancer survivors to determine if physical activity (dichotomized) predicted mean differences in negative mood and quality of life in this population. Methods Study participants include 114 women diagnosed with breast cancer (any stage of disease, any type of breast cancer) recruited to participate in an adaptive cognitive–behavioral stress management intervention. The mean body mass index of the sample at baseline was 31.39 (standard deviation = 7.17). Results A multivariate analysis of covariance (MANCOVA) was conducted to determine if baseline physical activity predicted mean differences in negative mood and quality of life at baseline and at follow ups while controlling for relevant covariates. A one‐way MANCOVA revealed a significant multivariate effect by physical activity group for the combined dependent variables at Time 2 (post 10‐week intervention), p = .039. The second one‐way MANCOVA revealed a significant multivariate effect at Time 3 (6 months after Time 2), p = .034. Specifically, Black breast cancer survivors who engaged in physical activity experienced significantly lower negative mood and higher social/family well‐being at Time 2 and higher spiritual and functional well‐being at Times 2 and 3. Conclusions Results show that baseline physical activity served protective functions for breast cancer survivors over time. Developing culturally relevant physical activity interventions specifically for Black breast cancer survivors may prove vital to improving quality of life and mood in this population. Copyright © 2016 John Wiley & Sons, Ltd.