Chronic Obstructive Pulmonary Disease (COPD) is a progressive pulmonary disorder underpinned by poorly reversible airflow resulting from chronic bronchitis or emphysema. The prevalence and mortality of COPD continue to increase. Pharmacotherapy for patients with COPD has included antibiotics, bronchodilators, and anti-inflammatory corticosteroids (but with little success). Oral diseases have long been established as clinical risk factors for developing respiratory diseases. The establishment of a very similar microbiome in the mouth and the lung confirms the oral-lung connection. The aspiration of pathogenic microbes from the oral cavity has been implicated in several respiratory diseases, including pneumonia and chronic obstructive pulmonary disease (COPD). This review focuses on current and future pharmacotherapeutic approaches for COPD exacerbation including antimicrobials, mucoregulators, the use of bronchodilators and anti-inflammatory drugs, modifying epigenetic marks, and modulating dysbiosis of the microbiome.