Background This randomized controlled pilot study evaluated the efficacy of osteopathic treatment in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD) assessed using spirometry, COPD Assessment Test (CAT) and six minutes walking test (6MWT). The main goals were to improve the quality of life of patients with stable moderate-to-severe COPD, and to revise the parameters of the assessment tests, such as spirometry and 6MWT. Methods The study comprised several phases and patients were divided into two groups: group A (controls) received conventional pharmacological treatment with Indacaterol-Glycopyrronium and, while group B (OMT group) received both traditional therapy and osteopathic manipulative treatment (OMT) at different stages of the study. The osteopathic approach focused on maxillary sinus, vertebral-pleural ligaments, phrenic nerves, ribs, pleura, lungs, bronchi, subclavian muscles, and trapezoid and conoid ligaments. Results Overall, 32 patients were randomized and treated. Patients of the OMT group got better improvements in all tests compared to the control group: spirometry: FVC (p<0.5411), total FEV1 (p<0.5061); CAT: OMT (p<0.0005) - controls (p<0.188) 6MWT OMT (p<0.0038) - controls (p<0.5326). The clinical results collected in phase (T3) confirm those obtained in the first sessions; the results of CAT questionnaire (p<0.0005) and 6MWT (p<O, OO38) highlighted score improvements of patients treated with osteopathy compared to patients in the other group. Conclusions The results showed that the patients with COPD who received the conventional pharmacological treatment in association with the OMT therapy demonstrated a good response to the osteopathic treatment, thus leading to significant improvements in their health and wellbeing, and a better daily functioning.