A global economic analysis of 12 dairy cattle diseases was conducted, estimating annual losses of $65 billion worldwide. The most costly diseases were subclinical ketosis ($18B), clinical mastitis ($13B), and subclinical mastitis ($9B). Other diseases, including clinical ketosis, displaced abomasum, dystocia, lameness, metritis, milk fever, ovarian cysts, paratuberculosis, and retained placenta, contributed smaller losses, ranging from $0.2B to $6B annually. Without adjusting for comorbidities, losses would have been overestimated by 45%. The United States, India, and China accounted for the largest losses, but the relative economic burden varied significantly depending on the measure used. Comorbidity adjustment reduced the estimated global losses to approximately $12 per person-year in milk-producing countries. The study highlights the importance of considering comorbidities in economic analyses to avoid overestimation. It also underscores the need for evidence-based animal health policies at the farm, national, and global levels to mitigate the economic impact of dairy cattle diseases. The findings emphasize the significant economic burden of these diseases on global dairy production and the necessity of addressing them through targeted interventions.A global economic analysis of 12 dairy cattle diseases was conducted, estimating annual losses of $65 billion worldwide. The most costly diseases were subclinical ketosis ($18B), clinical mastitis ($13B), and subclinical mastitis ($9B). Other diseases, including clinical ketosis, displaced abomasum, dystocia, lameness, metritis, milk fever, ovarian cysts, paratuberculosis, and retained placenta, contributed smaller losses, ranging from $0.2B to $6B annually. Without adjusting for comorbidities, losses would have been overestimated by 45%. The United States, India, and China accounted for the largest losses, but the relative economic burden varied significantly depending on the measure used. Comorbidity adjustment reduced the estimated global losses to approximately $12 per person-year in milk-producing countries. The study highlights the importance of considering comorbidities in economic analyses to avoid overestimation. It also underscores the need for evidence-based animal health policies at the farm, national, and global levels to mitigate the economic impact of dairy cattle diseases. The findings emphasize the significant economic burden of these diseases on global dairy production and the necessity of addressing them through targeted interventions.