In the present work, sensitive and selective determination of teriflunomide (Trf) on an edge plane pyrolytic graphite electrode (EPPGE) using differential pulse voltammetry (DPV) is presented for the first time. It was found that Trf gives a single well-defined oxidation peak at ca. +1.0 V vs. Ag/AgCl (3 mol L⁻¹ KCl) in Britton–Robinson buffer solution (BRBS) at pH 3.0. The optimization of pH and DPV parameters was performed. A linear response of Trf was obtained in the range of 2.5 × 10⁻⁶ to 5.0 × 10⁻⁵ mol L⁻¹ for EPPGE. The limit of detection (LOD) and limit of quantification (LOQ) were found to be 6.2 × 10⁻⁷ mol L⁻¹ and 2.1 × 10⁻⁶ mol L⁻¹, respectively. Furthermore, the proposed method was validated and successfully applied for the determination of Trf in the spiked samples of human urine with satisfactory recoveries in the range of 95.2–103.5% (RSD = 4.2%). The influence of potential interfering agents on the peak current response of Trf was also studied. Moreover, to understand the electrooxidation process of Trf on EPPGE, cyclic voltammetry (CV) was employed. Additionally, the surface topography and morphology of the EPPGE were characterized by atomic force microscopy (AFM) and scanning electron microscopy (SEM), respectively. The surface area of EPPGE was calculated based on the Randles–Sevcik equation.