The impact of ventilation efficiency on radon (222Rn) and carbon dioxide (CO2) concentrations in the indoor air of a residential building was studied by applying transient data analysis within the CONTAM 3.4 program. Continuous measurements of 222Rn and CO2 concentrations, together with basic meteorological parameters, were carried out in an apartment (floor area about 27 m2) located in Ljubljana, Slovenia. Throughout the experiment (October 3–15), frequent ventilation (several times per day), poor ventilation (once to twice per day) and no ventilation scenarios were applied, and the exact ventilation and occupancy schedule were recorded. Based on the measurements, a transient simulation of 222Rn and CO2 concentrations was performed for six sets of scenarios, where the design ventilation rate (DVR) varied based on the ventilation requirements and recommendations. On the days of frequent ventilation, a moderate correlation between the measured and simulated concentrations (r = 0.62 for 222Rn, r = 0.55 for CO2) was found. The results of the simulation indicated the following optimal DVRs: (i) 36.6 m3 h−1 (0.5 air changes per hour, ACH) to ensure a CO2 concentration below 1000 ppm and a 222Rn concentration below 100 Bq m−3; and (ii) 46.9 m3 h−1 (0.7 ACH) to ensure a CO2 concentration below 800 ppm. These levels are the most compatible with the 5C_Cat I (category I of indoor environmental quality, defined by EN 16798-1:2019) scenario, which resulted in concentrations of 656 ± 121 ppm for CO2 and 57 ± 13 Bq m−3 for 222Rn. The approach presented is applicable to various types of residential buildings with high overcrowding rates, where a sufficient amount of air volume to achieve category I indoor environmental quality has to be provided. Lower CO2 and 222Rn concentrations indoors minimise health risk, which is especially important for protecting sensitive and fragile occupants.