African American women with systemic lupus erythematosus (SLE) have worse disease outcomes compared to their White counterparts. Stressors associated with race may contribute to poorer health in this population through maladaptive behavioral pathways. This study investigated relationships between stress associated with anticipating racism, smoking, and SLE disease activity. Data were from 432 African American women with SLE in the Black Women’s Experiences Living with Lupus (BeWELL) Study. Controlling for sociodemographic and health-related covariates, multivariable regression analyses revealed a significant association between anticipatory racism stress (ARS) and disease activity (p = 0.00, b = 1.13, 95% CI [0.43, 1.82]). A significant interaction between ARS and smoking also indicated that smoking exacerbated the effect of ARS on disease activity (p = 0.04, b = 1.95, CI = 0.04, 3.96). Test for evidence of smoking mediating the effect of ARS on disease activity were not statistically significant (z = 1.77, p = 0.08). Findings have implications for future SLE disparities research among African American women with SLE.