The occurrence and potential toxicity of synthetic musks in environmental media have aroused concerns for the impacts of these chemicals on ecosystems and human health. Here, we present the first method using ultra-performance liquid chromatography-atmospheric pressure photoionization-tandem mass spectrometry (UPLC-APPI-MS/MS) for analysis of the six most important synthetic musks. Analysis was performed on an API 3000 triple quadrupole equipped with a PhotoSpray APPI source. Two pairs of precursor/product ions are presented that are essential for confirmation. Chromatographic separation is completed in 7 min in the positive mode and 5.1 min in the negative mode. Furthermore, three dopant solutions (0.5% anisole in toluene, 0.5% 2,4-difluoroanisole (DFA) in bromobenzene, and 0.5% DFA in chlorobenzene) are compared in terms of sensitivity, linearity, precision, and accuracy. The best sensitivity is associated with 0.5% anisole in toluene as the dopant; all LODs are below 6 pg. The linear range is 5 to 500 ppb with fairly good precision and accuracy. This analytical method has also proven its applicability by analyzing real air samples. In summary, we present a fast, sensitive, and reliable UPLC-APPI-MS/MS method for six important synthetic musks; it can be readily applied to environmental studies.