Cortex Lycii, the root barks of Lycium barbarum and L. chinense, known as “di gu pi” in traditional Chinese herbal drugs, is an important ingredient of formulations used for treating a variety of diseases. During the last 3 decades, more than 70 chemical entities have been separated and purified from either the aqueous or aqueous ethyl alcohol extracts of Cortex Lycii. In this study, high-performance liquid chromatography together with quadrupole-time-of-flight mass spectrometry (MS) was employed to explore new analog structures from aqueous ethyl alcohol extracts (50%, v/v), which led us to discover 4 new phenolic amides and a new cyclic peptide. The structure-based manual screening method, on the basis of the analysis of the fragmentation pathway of the previously known compounds, was used to make a preliminary analysis of the negative total ion chromatography and negative extract ion spectra. Three ions at m/ z 472.1, 314.1, and 445.2 were assigned to phenolic amides, and by further analysis of their MS/MS data, the structure of 1, corresponding to one of them ( m/ z 314.1), was illustrated as an analog of the known compound KN1. A parent ion at m/ z 856.1 was assigned to a cyclic peptide analog (2) in the manual analysis procedure. Furthermore, the MS/MS data were profiled on the Global Natural Product Social Molecular Networking (GNPS, https://gnps.ucsd.edu/ProteoSAFe/static/gnps-splash.jsp ) workflow to weave a visualization molecular network. Three more new analog ions ( m/ z 604.3 [3], 597.3 [4], and 611.3 [5]) were found in the aggregation of KN5 and KN7, and their structures were all determined by comparisons with known compounds. This manual and networking automatic screening method may provide a sensitive and efficient procedure to facilitate the mining of novel trace components.