Therefore, screening of active compounds in medicinal plants based on tumor microenvironment regulation may be a more specific and economical strategy than the conventional cytotoxicity-directed separation strategy. In the present study, TAMs/CXCL1 promoter activity-guided fractionation approaches were conducted to separate the bioactive compound in XIAOPI formula. This strategy was proved to be a promising and reliable screening technique by validating the antimetastatic effects of BHS in vitro and in vivo. Meanwhile, this bioactivity-guided fractionation approach also suggests BHS as one of the key reference compounds for quality control of XIAOPI formula.