Background/Objective: Clostridioides difficile infection (CDI) is a common healthcare-associated ailment, presenting major health and economic challenges, especially for the elderly. Despite its prevalence, comprehensive data about CDI’s impact on the elderly are limited. Methods: This study used the Global Burden of Disease Study 2019 data to analyze CDI trends from 2000 to 2019, considering factors like sex, region, and sociodemographic index (SDI). Results: This study revealed that CDI caused approximately 18,181 deaths and 252,709 disability-adjusted life years (DALYs) among the elderly worldwide. The Americas showed the highest CDI burden, while the Eastern Mediterranean saw the steepest rate increase from 2000 to 2019. Regions with a high SDI also displayed substantial CDI impact. Conclusions: The escalating burden of CDI in the elderly, especially in high-SDI areas and the Americas, emphasizes an urgent need for targeted public health strategies.