Background: Chronic obstructive pulmonary disease (COPD) is a disabling and often a progressive disease with multiple systemic effects, which is associated with limited functional capacity, impaired health status, depression, poor prognosis, and high risk of mortality. It has been cited that fat-free mass present in the skeleton muscle responsible for limitation in daily activities as well as exercise capacities. Aim and objectives: Study to assess the correlation of fat-free mass index (FFMI) with disease severity in COPD patients by conducting 6-min walk test (6MWT). Methods: A case–control, multi-group study designed with 150 subjects. Comprises in three groups—G1: 50 COPD patients; G2a: 50 apparently healthy smokers; and G2b: healthy nonsmokers. Pulmonary function test (PFT), 6MWT, and FFMI were conducted in all study subjects. Fat-free mass index measured by the bioelectrical impedance method. Chi-square/Fischer exact test, the Student t-test, and the Pearson correlation test were used to analyze data. p-value of < 0.05 was considered as statistically significant. Results: Fat-free mass index was significantly low among COPD subjects (14.41 ± 3.07) compared to healthy nonsmokers [15.89 ± 1.53 kg/m²; p = 0.003, odd ratio 7.58 (CI 3.112,19.56)]. Fat-free mass index has robust and significant positive correlation (r = 0.440; p = 0.001) with 6MWT in COPD patients. The Modified Medical Research Council Dyspnea score was found to have significant inverse relation with the fat-free mass in COPD patients. Conclusion: The study indicates that decrement in FFMI is significantly associated with risk of dyspnea and fatigability among COPD patients on physical activity compared with healthy control. Clinical significance: The study highlights that decrement in physical activity among COPD patients is due to loss of fat-free mass at significant level compared to healthy people, hence nutritional support as well as physical exercise is equally important as bronchodilator therapy in treatment plan.