Background: Crohn’s disease (CD) is an inflammatory bowel disease, cases of which have substantially increased in recent years. The classical formula Dajianzhong decoction (DD, Japanese: Daikenchuto) is often used to treat CD, but few studies have evaluated related therapeutic mechanisms. In this study, we investigated the potential targets and mechanisms of DD used for treating CD at the molecular level through the weighted gene co-expression network. Methods: The main chemical components of the three DD herbs (Zanthoxylum bungeanum Maxim., Zingiber officinale (Willd.) Rosc., and Ginseng Radix et Rhizoma) were searched for using the HERB database. The targets for each component were identified using the SwissTargetPrediction and HERB databases, whereas the disease targets for CD were retrieved from the GeneCards and DisGeNET databases. The functional enrichment analysis was performed on the common targets of DD and CD. High-throughput sequencing data for CD patients were retrieved from the Gene Expression Omnibus database, and WGCNA was performed to identify the key targets. The association between the key targets and DD ingredients was verified using molecular docking. Results: By analyzing the interaction targets between DD and CD, 196 overlapping genes were identified. The enrichment results indicated that the PI3K-AKT, TNF, MAPK, and IL-17 signaling pathways influenced the mechanism of action of DD in counteracting CD. Combined with WGCNA, four differentially expressed genes (SLC6A4, NOS2, SHBG, and ABCB1) and their corresponding 24 compounds were closely related to the occurrence of CD. Conclusions: By integrating gene co-expression network analysis, this study preliminarily reveals the internal molecular mechanism of DD in treating CD from a systematic perspective, validated by molecular docking. However, these findings require further validation.