Objective: To examine the long-term association of objectively measured moderate-to-vigorous physical activity (MVPA) and its longitudinal changes with progression to chronic kidney disease (CKD) in patients with type 2 diabetes (T2D) and overweight/obesity. Methods: This study included 1746 participants in the Look AHEAD trial with baseline estimated glomerular filtration rate (eGFR)≥60 mL/min/1.73 m2. MVPA was measured at baseline, year 1, year 4 and year 8 using an RT3 accelerometer. The outcome was progression to CKD, defined as eGFR<60 mL/min per 1.73 m2 with a drop of ≥30% or end-stage kidney disease. Cox hazards models were fitted to examine the association between MVPA and outcomes. Results: Over a median follow-up of 12.0 years, 567 participants experienced progression to CKD. Overall, there was a linear inverse association of cumulative average total MVPA (per 100 min/week higher amount, HR: 0.91; 95% CI: 0.86 to 0.96) and MVPA accumulated in bouts of ≥10 min (per 100 minutes/week higher amount, HR: 0.81; 95% CI: 0.72 to 0.91) with progression to CKD. Moreover, an increase in total MVPA from baseline to year 4 (the fourth quartile, ≥63.2 min/week) was associated with a 33% lower risk of progression to CKD compared with the largest MVPA reduction (the first quartile, <-198.3 min/week). A lower risk of progression to CKD was also observed for increases in MVPA accumulated in bouts of both <10 min and ≥10 min. Conclusions: Longer MVPA time and increases in MVPA was associated with a reduced risk of progression to CKD in adults with overweight/obesity and T2D.