Studying spontaneous airflow dynamics would help understand the adverse respiratory effects caused by increasing airway obstruction in chronic obstructive pulmonary disease (COPD). By using a multiscale sample entropy (MSE) analysis of airflow dynamics derived from spontaneous ventilation, we aimed to compare the system complexity between control subjects (n = 12) and COPD patients (n = 16). COPD patients revealed a significant decrease in MSE calculated in the whole range of studied scale factors (1 to 10; p = 0.0191), in the initial range (1 to 5; p = 0.0050), as well as in the final range (5 to 10; p = 0.0485). Correlation analysis showed that this complexity loss was associated with airway obstruction (p = 0.001). The obtained results are in close agreement with the involved physiology. In addition, the derived MSE parameters allowed adequate diagnostic accuracy (area under the receiver operating characteristic curve of 0.82). In conclusion, the system complexity of spontaneous airflow dynamics is reduced in COPD. This finding implies that the adaptability of the respiratory system is impaired in these patients, which may explain the exercise intolerance experienced by patients with COPD. In addition, COPD patients and control subjects could be adequately distinguished from MSE analysis of spontaneous airflow dynamics.