Based on the fingerprint of Lycii Cortex and combined with network pharmacology, potential quality marker (Q-Marker) of Lycii Cortex was screened under the guidance of the "Five Principles", and its quantitative analysis method was established to provide reference for quality control of Lycii Cortex. In this study, high performance liquid chromatography (HPLC) was used to establish the fingerprint of 20 batches of Lycii Cortex, and combined with chemometric analysis, the differential markers of Lycii Cortex from different origins were screened out, and then the core targets and key pathways of the characteristic components of Lycii Cortex were obtained by network pharmacology and other methods, and the "component target pathway" network was drawn to screen the core components of Lycii Cortex for the treatment of hypertension, hyperglycemia and hyperlipidemia (referred to as "three hypers"). Based on the "Five Principles", the potential Q-Marker for the treatment of "three hypers" by Lycii Cortex was finally screened out, and its quantitative analysis method was established by HPLC, and its content was determined. The fingerprint of Lycii Cortex was established, and 12 common peaks were identified. Six peaks were identified by the reference substance, which were N-caffeoylputrescine, feruloylputrescine, kukoamine B, kukoamine A, lyciumin A, and lyciumin B. According to the chemometrics analysis, N-caffeoylputrescine, feruloylputrescine, kukoamine B, kukoamine A, lyciumin A, and lyciumin B were selected as the differential markers of different origin. Furthermore, the network pharmacology analysis revealed three principal components: feruloylputrescine, kukoamine B, and kukoamine A. Additionally, key targets were identified, including the epidermal growth factor receptor (EGFR), mitogen-activated protein kinase 10 (MAPK10), MAPK8, MAPK14, estrogen receptor 1 (ESR1), and nitric oxide synthase 3 (NOS3). The analysis also highlighted significant cancer-related signaling pathways, such as those involved in cancer signaling, cancer proteoglycans, the MAPK signaling pathway, endocrine resistance, and the complement and coagulation cascade. These findings suggested potential therapeutic applications of Lycii Cortex in addressing the "three hypers" conditions. Based on the guidance of "Five Principles", this study finally screened out the potential Q-Marker of kukoamine A and kukoamine B for the treatment of "three hypers", and established the content determination method, with the content of 0.19% - 0.97% and 1.77% - 5.66%. Therefore, HPLC fingerprint of Lycii Cortex have been established, and combined with chemometrics and network pharmacology, the potential Q-Marker of Lycii Cortex in the treatment of "three hypers" was predicted, which provide scientific basis and reference for the quality control and quality evaluation of Lycii Cortex.