Diclofenac (DLF), a widely recognized non-steroidal anti-inflammatory drug (NSAID), and sulfamethoxazole (SMX), a broad-spectrum sulfonamide antibiotic, are commonly prescribed medications that have raised concerns as significant contributors to pharmaceutical pollution in natural ecosystems despite their clinical effectiveness. This study investigates the potential phytoremediation pathways for these two drugs in plant systems by tracking and quantifying the fate of the parent compounds and their metabolites in Arabidopsis thaliana using cell and seedling cultures. Results indicated significant differences in the dissipation of DLF according to the treatment and time interaction within the cell cultures. Viable plant cells showed complete dissipation of DLF from an initial concentration of 2758 ng/mL in 96 h, whereas non-viable cells and blank solutions remained stable. The dissipation of SMX was comparable across viable, non-viable, and blanks, showing a minor decrease from 842 to 799 ng/mL over 120 h following the treatment of viable cells. DLF metabolites including 4′-hydroxy-diclofenac, 5-hydroxy-diclofenac, acyl-glutamatyl-diclofenac, 1-(2,6-dichlorophenyl)-5-hydroxy-2-indolinone, 5-sulfooxy-diclofenac, 5-glucopyranosyloxy-diclofenac, 1-(2,6-dichloro-4-hydroxyphenyl)-2-indolinone, and 4′-glucopyranosyloxy-diclofenac were recognized, likely formed through acylation, glutamyl conjugation, hydroxylation, dehydration, cyclization, sulfonation, and glucosidation. While for SMX, metabolites including sulfamethoxazole-glucuronide, nitroso-sulfamethoxazole, N4-acetylsulfamethoxazole, and N4-acetyl-5-OH-sulfamethoxazole were identified, potentially produced through glucuronidation, nitrosation, acetylation, and hydroxylation. Phase I metabolite concentrations of DLF and SMX peaked earlier than those of phase II metabolites. Hydroponic A. thaliana demonstrated comparable efficiencies in the phytoremediation of DLF and SMX, with concentrations varying from 1 mg/L to 10 mg/L. Detectable levels of both parent compounds and their metabolites confirmed successful absorption and metabolism within the plant system. This study provides valuable insights into the potential of phytoremediation as a sustainable approach for reducing the environmental toxicity of DLF and SMX and suggests comparable metabolic efficiency. These findings contribute to the growing body of knowledge on phytoremediation and its application in addressing pollution from pharmaceuticals and personal care products. Display omitted •Cell cultures and hydroponic seedlings were incubated with diclofenac and sulfamethoxazole.•Metabolites and metabolism pathways of diclofenac and sulfamethoxazole have been identified.•Metabolites of DLF and SMX were qualified and quantified.•Arabidopsis thaliana showed comparable efficiency in metabolism and phytoremediation of DLF and SMX.