Purpose: Type 2 diabetes mellitus (T2DM) emphasizes the maintenance of high levels of physical activity and requires interventions tailored to the characteristics of each patient. We hypothesized that T2DM combined with diabetic kidney disease (DKD) could increase skeletal muscle fatigability, becoming a specific contributor to physical inactivity. This study aimed to determine the effects of DKD complications on fatigability and the relationship between fatigability and physical activity in patients with T2DM. Methods: The participants were 50 patients with T2DM aged 40–65 years with an estimated glomerular filtration rate of 30 ml/min/1.73 m2 or higher. An experimental protocol was performed using a isokinetic dynamometer to assess muscle function. Fatigability (maximal voluntary concentric contraction [ΔMVCC] velocity, maximal voluntary isometric contraction [ΔMVIC] torque) was calculated, indicating the decrease in angular velocity and muscle strength associated with the exercise task. The patient characteristics, physical activity (IPAQ-SV), knee extension strength, and skeletal muscle index were evaluated. Participants were divided into two groups (DKD and non-DKD) according to the presence or absence of DKD, and ΔMVCC velocity and ΔMVIC torque were compared. Results: ΔMVCC velocity was significantly higher in the DKD group than that in the non-DKD group (p<0.05). Similarly, ΔMVIC torque was significantly higher in the DKD group compared with the non-DKD group (p<0.05). Subgroup analysis showed that ΔMVCC velocity was independently associated with physical activity in the DKD group (odds ratio: 0.045, 95% confidence interval: 0.913–0.999). Conclusion: Fatigability increased with DKD in patients with T2DM and may be related to physical activity.