Objective: This work aims to investigate the incidence and mortality trends for mesothelioma in the Republic of Croatia from 2001 to 2021 and compare them with other populations. Methods: Data on the incidence and mortality of mesothelioma from 2001 to 2021 were taken from the databases of the Croatian Institute of Public Health. We calculated age-standardized incidence and mortality rates using the direct standardization method using the Standard European Population. Incidence and mortality trends were analyzed using the Joinpoint program, version 5.1.0. April 2024 Results: Despite an increase in incidence and mortality in the first part of the observed period, the second half of the 2010s saw a change in trends, with a statistically significant decline in incidence, followed by a consequent reduction in mortality. However, over the entire research period, there was an overall increase in the incidence of mesothelioma, particularly among men and the elderly population. Among those over 75 years old, the incidence rose by 210% in men and 273% in women. In 2021, the incidence of mesothelioma in Croatia was lower than the European Union average, but due to the later ban on asbestos use and reduced diagnostic activity during the COVID-19 pandemic, the possibility of a future increase in incidence cannot be excluded. Conclusion: Mesothelioma incidence trends in Croatia are similar to those in Western European countries with a historically developed shipbuilding industry. However, due to the relatively late introduction of the regulation of the use of asbestos in the professional environment, incidence and mortality trends in Croatia differ from those in the rest of the European Union. In the coming decades, a significant decrease in incidence and mortality is expected in all countries of the European Union.