The interaction between 5-fluorouracil (5-FU) and some rare earth metals namely samarium (III) and europium (III) was studied using UV–Visible spectrophotometry and high performance liquid chromatography (HPLC) with fluorescence detection. The synthesized complexes were characterized by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR) and liquid chromatography mass spectrometry (LC/MS/MS). UV–Vis spectroscopic data revealed that the binding between two trivalent lanthanides and 5-FU was static binding, with conditional binding constant  K_{(Sm−5−FU)} = 0.452 × 10⁴ M⁻¹ and K_{(Eu−5−FU)} = 0.183 × 10⁴ M⁻¹. Data were comparable with the values obtained using HPLC. The powder X-ray diffraction pattern of the complexes was used to determine the cell parameters and the hkl indices together with their corresponding 2θ values. The thermodynamic parameter ΔG° …