Background: COPD remains a leading cause of hospitalization and mortality worldwide. This study aimed to analyze trends in COPD patients in Spain from 2016 to 2023, compare outcomes between patients with COPD as a primary versus secondary diagnosis, and identify factors associated with in-hospital mortality. Methods: Retrospective observational study using the Spanish database CMBD. 711.799 patients were analyzed. Demographic characteristics, Charlson Comorbidity Index (CCI), complications, mortality, and hospitalization costs were also evaluated. Multivariate logistic regression was used to identify mortality risk factors. Results: The overall hospitalization rate was 20.02 per 1000 admissions. It decreased by 30% during 2020–2021 before rebounding to peak levels in 2023. The proportion of female patients increased from 19.9% (2016) to 26.4% (2023). Patients with COPD as a secondary diagnosis had higher mortality (13% vs. 5.4%, p < 0.001), greater comorbidity burden (mean CCI 3.5 vs. 2.8), and higher costs. While overall admissions dropped in 2020, mortality peaked at 11.7%, and the number of patients with extremely severe disease nearly doubled. Independent risk factors for mortality included sepsis, age ≥ 66 years, CCI ≥ 3, and COVID-19. Conclusions: Hospitalization involving COPD in Spain showed pandemic-related fluctuations with increasing clinical complexity and increasing female sex. The higher mortality and cost associated with secondary COPD diagnosis highlight the need for comprehensive risk stratification of comorbid conditions and multidisciplinary management of these patients. Early identification of sepsis and CCI scores is essential to improve clinical outcomes in the aging population.