The present study aimed to measure the mortality burden caused by premature death due to substance abuse in different geographical regions of Iran from 2014-17. In this serial cross-sectional study, the data related to individuals who had died of drug abuse were first collected from two sources (Iranian Ministry of Health and Medical Education and the Iranian Legal Medicine Organization). Then, using the capture-recapture method, the number of drug-related deaths was estimated. The years of life lost (YLLs) for all provinces of Iran was calculated based on age, sex, and year. During these four years, the total number of deaths was 12029. The mean age of the individuals was 37.3±14.1. The mean age of dead people was constant in women and men over this period; however, the mean age of dead women due to substance abuse was lower than that of men. The mean YLLs per dead person was 70131.3329 years for men and 9321.1125 years for women. The potential years of life lost (YLLs) showed an upward trend, which was stronger in women than men. It is necessary to perform more regional overviews for finding differences in the number of YLLs due to substance abuse so that specific regional policies can be adopted.