Background Smokeless tobacco (ST) is consumed by more than 300 million people worldwide. The distribution, determinants and health risks of ST differ from that of smoking; hence, there is a need to highlight its distinct health impact. We present the latest estimates of the global burden of disease due to ST use. Methods The ST-related disease burden was estimated for all countries reporting its use among adults. Using systematic searches, we first identified country-specific prevalence of ST use in men and women. We then revised our previously published disease risk estimates for oral, pharyngeal and oesophageal cancers and cardiovascular diseases by updating our systematic reviews and meta-analyses of observational studies. The updated country-specific prevalence of ST and disease risk estimates, including data up to 2019, allowed us to revise the population attributable fraction (PAF) for ST for each country. Finally, we estimated the disease burden attributable to ST for each country as a proportion of the DALYs lost and deaths reported in the 2017 Global Burden of Disease study. Results ST use in adults was reported in 127 countries; the highest rates of consumption were in South and Southeast Asia. The risk estimates for cancers were also highest in this region. In 2017, at least 2.5 million DALYs and 90,791 lives were lost across the globe due to oral, pharyngeal and oesophageal cancers that can be attributed to ST. Based on risk estimates obtained from the INTERHEART study, over 6 million DALYs and 258,006 lives were lost from ischaemic heart disease that can be attributed to ST. Three-quarters of the ST-related disease burden was among men. Geographically, > 85% of the ST-related burden was in South and Southeast Asia, India accounting for 70%, Pakistan for 7% and Bangladesh for 5% DALYs lost. Conclusions ST is used across the globe and poses a major public health threat predominantly in South and Southeast Asia. While our disease risk estimates are based on a limited evidence of modest quality, the likely ST-related disease burden is substantial. In high-burden countries, ST use needs to be regulated through comprehensive implementation of the World Health Organization Framework Convention for Tobacco Control.