<p>Isophorone diisocyanate (IPDI) is a common raw for the synthesis of advanced polyurethane materials, where the process is typically performed with butane-1,4-diol (BDO) as a chain extender. Thermal analysis is a powerful method for investigating the characteristics of materials and reactions for improving environmental performances and stability. Therefore, thermal behaviors of IPDI/BDO system were measured by combining differential scanning calorimetry (DSC) and vent sizing package 2 (VSP 2) for understanding the thermal hazard properties at various conditions. The results show that the average value of heat production is 478.83&#xa0;J&#xa0;g⁻¹ at three heating rates measured by DSC and the seriousness of the reaction is classified as “critical.” Then the apparent activation energies were determined using differential Friedman method. Furthermore, the detailed reaction models were established by matching the experimental data according to the method of multivariate nonlinear regression analyses. It was found that the reaction had the autocatalytic property. Then the established kinetic models were used to further predict thermal features under the isothermal and adiabatic conditions. Time to maximum rate under adiabatic condition (<i>TMR</i>_ad) is approximately equal to 74.1&#xa0;min measured by VSP 2 and the probability of reaction is “frequent” in such a reactor volume of about 410&#xa0;mL. All above findings provide valid data references for the thermal stability and safety management in laboratories and even in factories.</p>