The kinetics and the mechanism of the reaction of 4-hydroxy-2-pentanone (4H2P) with Cl atom were investigated using quantum theoretical calculations. Density functional theory, CBS-QB3, and G3B3 methods are used to explore the reaction pathways. Rice–Ramsperger–Kassel–Marcus theory is employed to obtain rate constants of the reaction at atmospheric pressure and the temperature range 278–400 K. This study provides the first theoretical and kinetic determination of Cl rate constant for reactions with 4H2P over a large temperature range. The obtained rate constant 1.47 × 10–10 cm3 molecule–1 s–1 at 298 K is in reasonable agreement with those obtained for C4–C5 hydroxyketones both theoretically and experimentally. The results regarding the structure–reactivity relationship and the atmospheric implications are discussed.