Abstract <p>The reaction of vanillin (Van) with baclofen (Bac) was studied kinetically in an aqueous acidic medium. The reaction product was examined using ¹H, ¹³C NMR and IR spectroscopy methods, in addition to ultra-performance liquid chromatography (UPLC). Moreover, the reaction was monitored spectrophotometrically, with (0.1–0.4) × 10^–4 mol/dm³ of Bac, (0.5–5.0) × 10^–2 mol/dm³ Van and 0.2–1.0 mol/dm³ ionic strength (<i>I</i>) over the temperature range of 40–60°C. The reaction is first order with respect to [Van] and [Bac], and the rate of the reaction decreases as pH increases in the range of 3.60–4.66. In addition, the effect of catalyst on the rate of the reaction was studied, and the thermodynamics activation parameters involving ∆<i>H</i>^* and ∆<i>S</i>^* were calculated. The rate of the reaction obeys the rate law <i>d</i>[Bac–Van]/<i>dt</i> = {<i>k</i>₂ + (<i>k</i>₄ + <i>k</i>₃[H⁺])[Van]} × [Bac]. This experimental rate law is consistent with a mechanism in which both the protonated and unprotonated forms of Van are involved in the rate-determining step, with the protonated species being the more reactive form. Furthermore, density functional theory (DFT) was performed to search the geometries of the final product resulting from the reaction between Bac and Van. Finally, interaction region indicator (IRI) calculations were used to reveal chemical bonding and weak interaction in the coupled compound Bac–Van.</p>