Background Patients with chronic obstructive pulmonary disease (COPD) often suffer concomitant disorders that worsen significantly their health status and vital prognosis. The pathogenic mechanisms underlying COPD multimorbidities are not completely understood, thus the exploration of potential molecular and biological linkages between COPD and their associated diseases is of great interest. Methods We developed a novel, unbiased, integrative network medicine approach for the analysis of the diseasome, interactome, the biological pathways and tobacco smoke exposome, which has been applied to the study of 16 prevalent COPD multimorbidities identified by clinical experts. Results Our analyses indicate that all COPD multimorbidities studied here are related at the molecular and biological level, sharing genes, proteins and biological pathways. By inspecting the connections of COPD with their associated diseases in more detail, we identified known biological pathways involved in COPD, such as inflammation, endothelial dysfunction or apoptosis, serving as a proof of concept of the methodology. More interestingly, we found previously overlooked biological pathways that might contribute to explain COPD multimorbidities, such as hemostasis in COPD multimorbidities other than cardiovascular disorders, and cell cycle pathway in the association of COPD with depression. Moreover, we also observed similarities between COPD multimorbidities at the pathway level, suggesting common biological mechanisms for different COPD multimorbidities. Finally, chemicals contained in the tobacco smoke target an average of 69% of the identified proteins participating in COPD multimorbidities. Conclusions The network medicine approach presented here allowed the identification of plausible molecular links between COPD and comorbid diseases, and showed that many of them are targets of the tobacco exposome, proposing new areas of research for understanding the molecular underpinning of COPD multimorbidities.