Ethnopharmacological　relevance:　Qingjie　Fuzheng　Granules　(QFG),　a　herbal　formula,　has　been　employed　as　an　adjuvant　therapy　for　colitis-associated　colorectal　cancer　(CAC),　yet　the　underlying　mechanisms　by　which　QFG　operates　remain　unclear.　Aims　of　the　study:　The　aim　of　this　study　is　to　investigate　whether　the　potential　mechanism　of　QFG　against　CAC　is　associated　with　macrophage　polarization.　Materials　and　methods:　Non-targeted　metabolomics　and　molecular　docking　assessed　potential　compounds　of　QFG　to　interact　with　targets　associated　with　macrophage　polarization.　A　model　of　AOM/DSS-induced　CAC　mice　was　established　to　analyze　the　effects　of　QFG　on　macrophage　polarization　using　flow　cytometry　and　immunohistochemical　staining.　In　vitro　experiments　involved　models　of　Ana-1　macrophages,　either　induced　by　varying　QFG　concentrations　or　with　MD2　knockdown,　to　analyze　M1-like　phenotype.　Meanwhile,　M2-like　macrophages　models　induced　by　IL-4　or　culture　supernatant　of　CT26　cells　were　utilized　to　assess　the　effects　of　QFG　on　M2-like　macrophages.　Finally,　the　mRNA　expression　of　M1-like　phenotype　related　to　TLR4　pathways　and　the　protein　expression　in　IL-4R-mediated　pathways　were　analyzed　using　RT-qPCR　and　Western　blot,　respectively.　Results:　Molecular　docking　confirmed　the　presence　of　binding　sites　between　the　ingredients　of　QFG　and　IL-4R　or　TLR4/MD2　receptor　complex.　QFG　could　induce　a　shift　in　macrophages　towards　an　M1-like　phenotype　while　inhibiting　an　M2-like　phenotype　in　the　colon　with　CAC　mice　and　Ana-1　macrophages.　QFG　resulted　in　the　upregulation　of　iNOS,　IL-6,　IL-1　beta,　and　TNF-alpha　mRNA　expression,　which　could　be　counteracted　by　TAK242,　SR11302,　INH14,　PDTC,　and　LY294002,　or　by　the　knockdown　of　MD2.　Meanwhile,　QFG　inhibited　IL-4R-induced　phosphorylation　of　STAT　6　and　Akt.　Conclusion:　Various　monomer　components　within　QFG　can　bind　to　MD2　or　IL-4R,　respectively,　thereby　inducing　macrophages　towards　an　M1-like　phenotype　through　TLR4-mediated　NF-kappa　B,　MAPK,　and　PI3K/Akt　pathway　activation,　or　inhibiting　macrophages　towards　an　M2-like　phenotype　via　IL-4R-mediated　JAKs　pathway　inhibition,　ultimately　exerting　an　inhibitory　effect　on　the　occurrence　and　development　of　CAC.