Background: Examine whether white blood cells (WBC) mediates the relationship between physical activity (PA) and insulin resistance in the broader population (objective 1), as well as the relationship between PA and chronic kidney disease (CKD) among those with diabetes (objective 2). Methods: Data from the 2003-2006 NHANES study was used, with 3,477 adults examined in objective 1 and 811 adults with diabetes examined in objective 2. Participants wore an ActiGraph 7164 accelerometer to measure PA; insulin resistance was assessed using the Homeostasis Model Assessment; and CKD was assessed from the Chronic Kidney Disease Epidemiology equation. Results: Regarding objective 1, and after adjustments, there was an inverse association between light-intensity physical activity (LPA) and WBC (b = -0.001; 95% CI: -0.002 to - 0.0006), with WBC, in turn, positively associated with insulin resistance (b = 0.02; 95% CI: 0.003 to 0.03). Regarding objective 2, LPA was inversely associated with WBC (b = -0.003; 95% CI: -0.005 to -0.0008), with WBC, in turn, associated with CKD (OR = 1.13; 95% CI: 1.01-1.27). Conclusions: These findings suggest that PA may be associated with insulin resistance and diabetes-induced chronic kidney disease through modulation of inflammation.