Background: This study aimed to investigate the mediating effect of physical activity (PA) on the relationship between average sleep duration and risk of stroke in suburban residents without stroke. Methods: A cross-sectional study was executed, and participants were recruited through a multistage, stratified, probability-proportional-to-size sampling method in this research. The stroke risk was measured using a risk assessment form for a high-risk stroke population. The PA score was calculated by the Physical Activity Rating Scale-3 (PARS-3). The average sleep duration was calculated by adding up night sleep and afternoon nap durations. A multiple linear regression analysis was conducted to identify the association between stroke risk, average sleep duration, and PA. The direct and indirect effects of average sleep duration on stroke risk were analyzed by using the PA in a mediation framework. Results: A total of 5312 suburban residents (average: 54.96 ± 12.21 years, 2970 women) participated in the study. After adjusting for covariates, relatively inappropriate sleep duration (8 h~9 h/>9 h) and stroke risk were significantly associated, compared with the moderate average sleep duration (7~8 h) (β = 0.038, 95% CI: 0.024~0.128; β = 0.078, 95% CI: 0.128~0.250; β = 0.150, 95% CI: 0.390~0.549). The PA total score (indirect effect ab = 0.013, 95% CI: 0.003~0.022) partially mediated the relationship between the long average sleep duration and stroke risk, in which the activity intensity (ab = −0.015, 95% CI: −0.021~−0.008), the activity duration (ab = 0.043, 95% CI: 0.029~0.058), and the activity frequency (ab = 0.012, 95% CI: 0.004~0.020; ab = 0.037, 95% CI: 0.026~0.050) all played a mediating role in the different sleep duration. Conclusions: A significant relationship between a long average sleep duration and stroke risk factors among people without stroke was found in this study. The PA and its components partially mediated the association between a long average sleep duration and stroke risk. Suitable prevention methods and interventions for PA and sleep may reduce the risk of stroke.