Ambient particulate matter (PM) is the major environmental concern in Tehran, Iran. Exposure to such particles is a serious global health concern and substantial evidence indicates that exposure to particulate matter contributes to cardiovascular and respiratory disease. Here, we provide a detailed health impact of ambient air pollution in Tehran by linking PM pollution with mortality caused by cardiovascular and respiratory disease. Air quality data of PM obtained from Tehran Air Quality Monitoring Stations (TAQMSs) during 2012–2017. Data mining methods conducted by Spatio-temporal outlier detection and “Air Pollution and Health: a European Approach (APHEA) project” was applied to impute missing values. Time-series data were analyzed to estimate the associations between PM pollution and cause-specific mortality at different lags in Tehran. Based on descriptive analysis, PM2.5 is expected to be a major influencing factor in the increased cardiovascular-related death (CVD) and respiratory dysfunction related death (RD) deaths. The cross-correlation analysis showed the same source for PM2.5 and PM10 in the ambient air of Tehran. Also, the results indicated delays of about 7–15 days from the increased concentrations of PMs and the observed rising in CVD and RD death. Trend analysis showed a more decreasing trend for PM2.5 pollutions than PM10 pollution and a slightly increasing trend for cause-specific deaths during 2012–2017. Long term exposure to high PM levels increases the CVD and RD deaths and control strategies along with control regulations should be considered to control PM.