Sprinkler activation is one of the key events defining the course of a compartment fire. The time when activation occurs is commonly used in the determination of the design fire scenario, which is the cornerstone of the design of building fire safety features. A well-known model of sprinkler activation (response time index (RTI) model) was introduced into the numerical scheme of the ANSYS Fluent computational fluid dynamics (CFD) package. The novel way in which the model is used is the calculation of the time for sprinkler activation within each discrete cell of the domain. The proposed novel approach was used in a case-study to assess the effects of comfort mode natural ventilation on a sprinkler’s activation pattern. It was found that hinged vents in the comfort mode had a significant effect on sprinkler activation, both in terms of delaying it as well as limiting the total number of cells in which the sprinkler would have activated. In some scenarios with a hinged vent, no activation was observed in the central point of the vent, possibly indicating problems with the autonomous triggering of the fire mode of such a device. It was also found that the RTI and C (related to the conductive transport of sprinkler fitting) parameter values had a moderate influence on sprinkler activation time—only for high-temperature sprinklers (≥ 141 °C). This study shows the applicability of the 3D activation time mapping for research focused on the fire safety of sprinkler-protected compartments and for the performance-based approach to sprinkler system design. Even though the RTI model is the industry standard for the determination of sprinkler response, the model implementation in ANSYS Fluent was not validated. This means that sources of uncertainty, mainly connected with the determination of flow velocity and temperature are not known, and the model should be used with caution. An in-depth validation is planned for subsequent studies.