Chronic obstructive pulmonary disease (COPD) is a very common and frequently fatal airway disease. Current therapies for COPD depend mainly on long-acting bronchodilators, which cannot target the pathogenic mechanisms of chronic inflammation in COPD. New pharmaceutical therapies for the inflammatory processes of COPD are urgently needed. Several anti-inflammatory targets have been identified based on increased understanding of the pathogenesis of COPD, which raises new hopes for targeted treatment of this fatal respiratory disease. In this review, we discuss the recent advances in bioactive low-molecular-weight drugs (LMWDs) for the treatment of COPD and, in addition to the first-line drug bronchodilators, focus particularly on low-molecular-weight anti-inflammatory agents, including modulators of inflammatory mediators, inflammasome inhibitors, protease inhibitors, antioxidants, PDE4 inhibitors, kinase inhibitors, and other agents. We also provide new insights into targeted COPD treatments using LMWDs, particularly small-molecule agents.