Sijunzi decoction (SJZD) is a traditional Chinese medicine prescription for the prevention and treatment of colorectal cancer. Our study is aimed to identify the potential therapeutic target of SJZD. Microarray analysis was performed on the patients with colorectal cancer under treatment of SJZD. The mRNA targets of SJZD were predicted by BATMAN-TCM database and were further identified by integrated analysis of expression data from TCGA. The correlation of gene expression and clinical characteristics was analyzed. Microarray analysis indicated that Krüppel-like factor 4 (KLF4) was significantly upregulated after intervention of SJZD. BATMAN-TCM prediction showed that KLF4 was an mRNA target of SJZD and it was downregulated in colorectal cancer by integrated analysis of expression data from TCGA. KLF4 may act as an administered indicator to assess whether adjuvant postoperative pharmaceutical therapy is needed for patients with colorectal cancer. Low KLF4 expression was significantly correlated with reductions of overall survival and recurrence rate. Our results suggested that KLF4 may be the potential therapeutic target of SJZD for the treatment of colorectal cancer.