Colorectal cancer emerges as one of the leading public health issues in Indonesia, which currently ranked third as the most common cancer with a 10 % mortality rate. The aberrant activation of Hedgehog signalling pathway is one of the mechanisms that can happen during colorectal cancer formation, which involving Smoothened (Smo) protein, a G protein-coupled receptors (GPCR) that plays an imperative role when this signalling pathway is mutated, leading into the massive growth of cancer stem cells. In this research, the Smo protein was employed against 41,399 flavonoid ligands through pharmacophore-based virtual screening and molecular docking simulation in order to find the most potential flavonoid compound as Smo protein inhibitor. All flavonoid compounds were subjected to computational toxicity and druglikeness predictions before they underwent screening and docking simulations. The result showed that the pharmacophore feature of Smo binding site was contained of three pharmacophore points; one H-donor feature, one H-acceptor feature, and one-aromatic feature, according to the vismodegib binding mode. In the end, about six flavonoid ligands were chosen as the best flavonoid compounds due to their molecular interactions and binding affinities in the binding site of Smo protein, with 3-methyl-4-oxo-2-phenyl-N-(tetrahydro-2-furanylmethyl)-4H-chromene-8-carboxamide, a modified-flavone compound, was chosen as the best flavonoid ligand to inhibit Smo protein by having ΔGbinding and RMSD values of -10.6934 kcal/mol and 0.9838 Å, respectively.