Because almost every traditional Chinese medicine (TCM) is a multicomponent system, QC of TCMs always involves various difficulties. As a current popular quality assessment approach, focusing on qualitative and quantitative analysis of certain compounds contained in herbal medicine has been widely used for the sake of expediency rather than being a practical and realistic way. However, this method does not take the existence of other constituents into account. Comparatively, the chromatographic fingerprint of the components is a more suitable approach to holistically assess the quality of herbal drugs. Fructus xanthii is a well-known herbal drug listed in all editions of the Chinese Pharmacopoeia. However, there is no quality evaluation method given in its monograph, even for the above-mentioned expediency. This paper reports an HPLC fingerprinting method for quality evaluation of F. xanthii. The HPLC profiles of 27 batches of commercial samples were further analyzed using chemometric methods, including similarity evaluation and principal component analysis. As a result, the established HPLC fingerprint contained 23 characteristic peaks; therein, 13 peaks were unambiguously assigned by comparing their retention times and UV spectra with those of reference compounds, and five peaks were tentatively identified on the basis of their MS/MS fragmentation patterns and UV spectra. Moreover, it could be clearly observed that caffeoylquinic acid and its analogs predominate in F xanthii. Except for three samples identified as outliers, 24 other commercial samples displayed similar HPLC profiles, indicating that the quality of the herbs from different markets is stable and consistent.