New, simple, rapid and precise reversed-phase high-performance liquid chromatographic method was developed for the simultaneous determination of orphenadrine citrate, caffeine and aspirin in presence of aspirin degradation products, orphenadrine citrate and caffeine process related impurities, and excipients. Good resolution and quantization were achieved on reversed-phase column [Phenomenex™ Luna ODS C₁₈ (25 cm×4.6 mm, 5 µm particles)]. Gradient elution based on; eluant [A]: 0.1% triethylamine in aqueous potassium dihydrogen phosphate buffer (50 mM; pH 3.0), while as, eluant [B]: acetonitrile, at a flow rate of 1.5 mL min⁻¹. UV quantitation was set at 215 nm. Linearity was exhibited for orphenadrine citrate, caffeine and aspirin within 0.5–150, 0.5–360 or 0.7–301 µg mL⁻¹ ranges, respectively. Satisfactory validation results were ascertained in terms of low limits of quantiation (6.33×10⁻²–7.94×10⁻²), mean percentage recovery (98.9–101.4%), precision (<2%) and robustness. The proposed method was proved to be specific, robust and accurate for the determination of cited drugs in pharmaceutical preparations in presence of their degradation products.