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Background: Derris scandens (DS) has been used in Thai traditional medicine recipes for musculoskeletal pain relief in Southern Thailand. Changing of terrain and climate affected its phytochemical constituents and led to change antioxidant and toxic properties. Objective: The aim of this study was to study phytochemical contents, antioxidant properties, and toxicity of the DS extracts' in vitro models. Materials and Methods: The DS ethanolic extract (EE) was partially extracted with chloroform (CE), ethyl acetate (EAE), and water (aqueous extract [AE]). Phytochemical contents, antioxidant properties, and toxicity in Caco-2 cells, peripheral blood mononuclear cells (PBMCs), and red blood cells (RBCs) were explored. Results: Genistein and gallic acid were rich in the EE and CE. The CE demonstrated the highest 2,2 − diphenyl − 1 − picrylhydrazyl scavenging activity with half-maximal Radical cavenging concentration (SC50) value – 0.81 ± 0.07 mg/mL. The EE showed the highest 2, 2'−azino − bis (3 − ethylbenzothiazoline − 6 − sulfonic acid) radical scavenging activity (SC50 = 22.05 ± 3.91 μg/mL) and all the extracts strongly inhibited lipid peroxidation. The EE and CE were more toxic than the EAE on Caco-2 cells with IC50 values – 26.45 ± 3.57 and 36.36 ± 6.87 μg/mL, respectively. At high dose, all fractions were not toxic to human's PBMCs, but they slightly induced RBC hemolysis by 3-6 percent. Conclusions: The DS grown in Southern Thailand had antioxidant properties, toxic to Caco-2 cells and not toxic to normal cells. High dose and continuous consumption of the DS must be concerned. Further safety assessment models including animals and humans should be performed to find safety dose of the DS. Abbreviations Used: ABTS: 2, 2-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid), DMEM: Dulbecco's Modified Eagle Medium, DMSO: Dimethyl sulfoxide, DPPH: 2,2-diphenyl-1-picrylhydrazyl, HLM: Human liver microsome, HLM: Human liver microsome, HPLC: High-performance liquid chromatography, IC50: Half inhibitory concentration, MDA: Malondialdehyde, OD: Optical density, PBMC: Peripheral blood mononuclear cell, RBC: Red blood cell, RPMI: Roswell Park Memorial Institute Medium, SC50: Halfmaximal radical scavenging concentration, SRB: Sulforhodamine B assay.