Nitrosamine impurities in pharmaceutical products require highly sensitive and reliable analytical methods because of their potential carcinogenicity and stringent regulatory acceptable intake limits. Although several LC–MS/MS methods have been reported for varenicline, simultaneous quantification of multiple nitrosamines in finished dosage forms with comprehensive validation and evaluation of matrix effects remains limited. In this study, a simple, sensitive, and risk-based APCI-LC-MS/MS method was developed and validated for the simultaneous determination of six nitrosamine impurities, namely N-nitroso varenicline, NDMA, NDEA, NEIPA, NDIPA, and NDBA, in varenicline tablet formulation. Chromatographic separation was achieved on conventional 5 µm Inertsil C18 column, compatible with standard HPLC instrumentation, using gradient elution with 0.1% formic acid in water and methanol, coupled to tandem mass spectrometry in positive APCI mode. The analytical procedure employed a simple methanolic extraction, extensive sample clean-up, with no isotope-labelled internal standards, while providing negligible matrix effects and efficient chromatographic separation within 30 min. The method was comprehensively validated according to International Council on Harmonization (ICH Q2(R2)) guidelines for specificity, sensitivity, matrix effect, linearity, precision, accuracy, robustness, solution stability, and filter compatibility. These parameters met the predefined acceptance criteria that demonstrates the reliability of the method for trace-level quantification of nitrosamines. The proposed method provides simultaneous multi-analyte determination, easy sample preparation steps, complete validation, and applicability to finished pharmaceutical products. The method is suitable for routine quality control. Four complementary analytical metrics: the Analytical GREEnness Metric (AGREE), the Analytical GREEnness Metric for Sample Preparation (AGREEprep), the Blue Applicability Grade Index (BAGI), and the Red Analytical Procedure Index (RAPI) were used to comprehensively evaluate the environmental sustainability and practical applicability of the developed LC–MS/MS method.