BackgroundThe present study aimed to investigate the sequence-dependent anticancer effects of combined treatment with sorafenib (Sora), a Food and Drug Administration-approved multikinase inhibitor drug, and plant-derived phytochemicals (PPCs) on human colorectal cancer (CRC) cell growth, and proteins associated with the control of cell cycle and apoptosis.MethodsThe cytotoxic effects of 14 PPCs on CRL1554 fibroblast cells were determined using an MTT assay. Moreover, the cytotoxicity of Sora, PPCs, and a combination of both on CRC cells were also investigated. Cell cycle analysis was performed using flow cytometry, and cell apoptosis was investigated using DNA fragmentation, Annexin V/propidium iodide double staining, and mitochondrial membrane potential analyses. The cell cycle- and apoptosis-associated protein expression levels were analysed using western blotting.ResultsBased on their low levels of cytotoxicity in CRL1554 cells at ≤ 20%, curcumin, quercetin, kaempferol, and resveratrol were selected for use in subsequent experiments. The combined treatment of sora and PPCs caused levels of CRC cytotoxicity in a dose-, cell type-, and schedule-dependent manner. Moreover, the combined treatment of CRC cells arrested cell growth at the S and G2/M phases, induced apoptotic cell death, caused extensive mitochondrial membrane damage, and altered the expression of the cell cycle and apoptotic proteins.ConclusionsResults of the present study highlighted a difference in the level of sora efficacy in CRC cells when combined with PPCs. Further in vivo and clinical studies using the combined treatment of sora and PPCs are required to determine their potential as a novel therapeutic strategy for CRCs.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12906-023-04032-6.