Sulfur-fumigation may induce chemical transformation of medicinal herbs. Development of rapid method to reveal potential sulfur-fumigation induced chemical transformation of herbs is a very important issue for efficacy and safety of herb application. In present study, a new strategy was proposed to rapidly reveal chemical transformation of sulfur-fumigated herbs by ultra-high-performance liquid chromatography–quadrupole/time of flight mass spectrometry (UHPLC–QTOF-MS/MS) based chemical profiling approach. The non-fumigated herb was water-wetted and further treated with burning sulfur to get sulfur-fumigated herb. Then the chemical fingerprints of both non-fumigated and sulfur-fumigated samples were compared by UHPLC–QTOF-MS/MS analysis. The identities of all detected peaks, in particular those newly generated in sulfur-fumigated samples were confirmed by comparing the mass spectra and retention times of peaks with that of reference compounds, and/or tentatively assigned by matching empirical molecular formula with that of published compounds, and/or elucidating quasi-molecular ions and fragment ions referring to available literature information. The identification could be rationalized through deducing possible reactions involved in the generation of these newly detected compounds. The proposed strategy was extensively investigated in the case of white ginseng. Total 82 components were detected in non-fumigated and sulfur-fumigated white ginseng samples, among them 35 sulfur-containing compounds detected only in sulfur-fumigated white ginseng and its decoction were assigned to be sulfate or sulfite derivatives of original ginsenosides, and were deduced to be generated via reactions of esterification, addition, hydrolysis and dehydration during sulfur-fumigation and decocting of white ginseng. The established approach was applied to discriminate sulfur-fumigated white ginseng among commercial samples from America, Canada, and Hong Kong SAR, Macau SAR and Mainland of China, which indicated that the proposed approach is rapid and specific, and should also be useful for investigation of potential chemical transformation of other sulfur-fumigated medicinal herbs.