Habitual coffee consumption has been associated with multiple health benefits. A comprehensive analysis of disease trajectory and comorbidity networks in relation to coffee consumption is, however, currently lacking.We aimed to comprehensively examine the health outcomes associated with habitual coffee consumption, through clarifying its disease trajectory and comorbidity networks.Based on the UK Biobank cohort, we included 395,539 individuals with available information on coffee intake collected at recruitment between 2006 and 2010. These individuals were categorized as having low (<1 cup per day), moderate (1-3 cups), and high (≥4 cups) levels of coffee intake, and were followed through 2020 to ascertain 496 medical conditions. Cox regression was used to assess the associations between high-level coffee intake and the risk of medical conditions with a prevalence ≥0.5% in the study population, after adjusting for multiple confounders, using low-level coffee intake as the reference. Disease-trajectory and comorbidity network analyses were then applied to visualize the temporal and nontemporal relationships between the medical conditions that had an inverse association with high-level coffee intake.During a median follow-up of 11.8 years, 31 medical conditions were found to be associated with high-level coffee intake, among which 30 showed an inverse association (HRs ranged from 0.61 to 0.94). The inverse associations were more pronounced for women, compared with men. Disease-trajectory and comorbidity network analyses of these 30 conditions identified 4 major clusters of medical conditions, mainly in the cardiometabolic and gastrointestinal systems, among both men and women; 1 cluster of medical conditions following alcohol-related disorders, primarily among men; as well as a cluster of estrogen-related conditions among women.Habitual coffee consumption was associated with lower risks of many medical conditions, especially those in the cardiometabolic and gastrointestinal systems and those related to alcohol use and estrogen regulation.© The Author(s) 2022. Published by Oxford University Press on behalf of the American Society for Nutrition.