BACKGROUND: Chronic obstructive pulmonary disease (COPD) often coexists with various systemic diseases, forming a comorbid condition. The causal evidence from Mendelian randomization (MR) studies on the impact of comorbidities on COPD is accumulating, yet information for comprehensive summary is limited. OBJECTIVES: This study aimed to systematically summarize the evidence from MR studies on the impact of comorbidities on COPD. DESIGN: Systematic review and meta-analysis of MR studies. DATA SOURCES AND METHODS: Eight electronic databases were searched to identify relevant MR studies about comorbidities associated with COPD from inception to June 3, 2024. Strengthening the Reporting of Observational Studies in Epidemiology-Mendelian Randomization (STROBE-MR) guidelines were used for reporting quality assessment. We used either a random-effects model or a fixed-effects model to estimate pooled causal evidence from MR studies of comorbidities and COPD. RESULTS: A total of 26 studies were included, of which 8, 4, and 3 studies summarized the causal effects of GERD, depression, obesity on the risk of COPD, respectively. Overall, the studies included had high reporting quality. Our meta-analysis using inverse variance weighted (IVW) of main MR analyses revealed positive causal effects of GERD (OR: 1.64; 95% CI: 1.47-1.84), depression (OR: 1.31, 95% CI: 1.01-1.71), and obesity (OR: 1.51; 95% CI: 1.25-1.83) on COPD. Our qualitative analysis also identified multisystem diseases such as asthma, bronchiectasis, peptic ulcers, heart failure, hypertension, rheumatoid arthritis, and osteoarthritis, as well as systemic conditions like anemia and frailty, were related to the risk of COPD. CONCLUSIONS: This study revealed the causal effects of comorbidities on COPD, providing new scientific evidence for the prevention and treatment of COPD, and aiding in the guidance of effective clinical strategies. REGISTRATION: This systematic review and meta-analysis protocol was prospectively registered with PROSPERO (No CRD42024575341).