Background: Ultra-processed food (UPF) is a popular supplement in the UK and other developed countries. However, whether and how UPF intake is associated with chronic obstructive pulmonary disease (COPD) remains unclear. Objective: We aimed to examine the association between UPF consumption and COPD incidence and explore the potential mediating effects of COPD-related biomarkers. Methods: This prospective cohort study included 207 002 participants without COPD at recruitment and completed 24-hour dietary recalls. UPF was defined according to the NOVA classification system. Incident COPD was ascertained using electronic hospital and mortality records. Cox regression models were used to estimate UPF consumption and the subsequent risk of COPD. Substitution analysis was performed to assess the risk of COPD by substituting UPF with an equivalent proportion of unprocessed or minimally processed food (UNPF). Mediation analyses were performed to evaluate the contribution of biomarkers related to the lipid profile, glucose metabolism, and systemic inflammation to the observed associations. Results: During a median follow-up of 13.1 (interquartile range: 12.5-13.9) years, 4670 COPD events were recorded. The adjusted hazard ratio (HR) of COPD in the highest quintile versus the lowest quintile of the UPF consumption proportion (weight percentage of the UPF) was 1.22 (95% confidence interval [CI]: 1.11-1.34). There was a 10% elevated risk of COPD incidence per SD increase in UPF intake (HR: 1.10; 95% CI: 1.08-1.13). Replacing 20% of the UNPF weight with the UPF was associated with a 13% decrease in COPD risk (95% CI: 0.84-0.91). In mediation analyses, biomarkers explained 1.0-10.1% of the association between UPF intake and COPD. Results from stratified and sensitivity analyses further support the robustness of these findings. Conclusions: Elevated UPF consumption was associated with a higher risk of COPD, and this association was primarily mediated by glucose, inflammation, and lipids, whereas substituting UNPF for UPF was associated with a decreased risk of COPD.