Identifying risk factors for cancer initiation and progression is the cornerstone of the preventive approach to cancer management and control (EPMA J. 4(1):6, 2013). Tobacco smoking is a well-recognized risk factor for initiation and spread of several cancers. The predictive, preventive, and personalized medicine (PPPM) approach to cancer management and control focuses on smoking cessation as an essential cancer prevention strategy. Towards this end, this study examines the temporal patterns of cancer burden due to tobacco smoking in the last three decades at global, regional, and national levels. The data pertaining to the burden of 16 cancers attributable to tobacco smoking at global, regional, and national levels were procured from the Global Burden of Disease 2019 Study. Two main indicators, deaths and disability-adjusted life years (DALYs), were used to describe the burden of cancers attributable to tobacco smoking. The socio-economic development of countries was measured using the socio-demographic index (SDI). Globally, deaths due to neoplasms caused by tobacco smoking increased from 1.5 million in 1990 to 2.5 million in 2019, whereas the age-standardized mortality rate (ASMR) decreased from 39.8/100,000 to 30.6/100,000 and the age-standardized DALY rate (ASDALR) decreased from 948.9/100,000 to 677.3/100,000 between 1990 and 2019. Males accounted for approximately80% of globaldeaths and DALYs in 2019. Populous regions of Asia and a few regions of Europe account for the largest absolute burden, whereas countries in Europe and America have the highest age-standardized ratesof cancers due to tobacco smoking. In 8 out of 21 regions, there were more than 100,000 deaths due to cancers attributable to tobacco smoking led by East Asia, followed by Western Europe in 2019. The regions of Sub-Saharan Africa (except southern region) had one of the lowest absolute counts of deaths, DALYs, and age-standardized rates. In 2019, tracheal, bronchus, and lung (TBL), esophageal, stomach, colorectal, and pancreatic cancer were the top 5 neoplasms attributable to tobacco smoking, with different burdens in regions as per their development status. The ASMR and ASDALR of neoplasms due to tobacco smoking were positively correlated with SDI, with pairwise correlation coefficient of 0.55 and 0.52, respectively. As a preventive tool, tobacco smoking cessation has the biggest potential among all risk factors for preventing millions of cancer deaths every year. Cancer burden due to tobacco smoking is found to be higher in males and is positively associated with socio-economic development of countries. As tobacco smoking begins mostly at younger ages and the epidemic is unfolding in several parts of the world, more accelerated efforts are required towards tobacco cessation and preventing youth from entering this addiction. The PPPM approach to medicine suggests that not only personalized and precision medicine must be provided to cancer patients afflicted by tobacco smoking but personalized and targeted preventive solutions must be provided to prevent initiation and progression of smoking. The online version contains supplementary material available at 10.1007/s13167-022-00308-y.