A sensitive and accurate method for the quantification of 1′-Demethyl-1′-nitrosonicotine (NNN) and 4-(methylnitrosamino)-1-(3-Pyridyl)-1-butanone) (NNK) in indoor air was developed and validated. To this aim, a novel approach for the collection of two tobacco-specific nitrosamines, using silica sorbent cartridges followed by simplified sample preparation and isotope dilution liquid chromatography/electrospray ionization tandem mass spectrometry, was applied. This procedure led to a substantial improvement in terms of sensitivity and sample throughput as compared with methods using conventional trapping. For the validation, a matrix-based approach using an accuracy profile procedure was selected. The evaluated matrices were background air samples, environmental aerosols of a heat-not-burn tobacco product (Tobacco Heating System [THS] 2.2, commercialized under the brand IQOS®), a rechargeable electronic cigarette (Solaris®), and the environmental tobacco smoke (ETS) of a conventional cigarette (Marlboro Gold®). The method showed excellent recoveries, sensitivity, and precision. The limits of detection of the method for NNN and NNK were 0.0108 ng/m3 and 0.0136 ng/m3, respectively. The calibration range of the instrument spanned 0.2–60 ng/mL. The calculated lower working range limit (LWRL) of the method for NNN was 0.126 ng/m3, and the LWRL for NNK was 0.195 ng/m3. The method was applied to evaluate surrogate environmental aerosols generated using smoking machines. This model is reliable but gives a large overestimation of the possible impact of THS 2.2 and e-cigarettes on indoor air, because the retention of NNN and NNK in the body of the consumers is not taken into account. As a consequence, the values reported do not reflect a real-life setting. The contents of the two target compounds in the surrogate environmental aerosols were 0.0830 ± 0.0153 ng/m3 of NNN and 0.0653 ± 0.0138 ng/m3 of NNK for THS 2.2, 0.0561 ± 0.0296 ng/m3 of NNN for e-cigarettes, and 0.816 ± 0.109 ng/m3 of NNN and 4.13 ± 1.04 ng/m3 NNK for cigarettes. These values correspond to 10% of the measured ETS concentration for NNN in environmental aerosols of THS 2.2 and 7% for those of e-cigarettes. For NNK, the value for the environmental aerosol of THS 2.2 was 2% of the ETS value.