Reactive carbonyl species including methylglyoxal (MGO) are oxidation metabolites of glucose and precursors of advanced glycation end products (AGEs). They are important mediators of cellular oxidative stress and exacerbate skin complications. Published data supports that certain phenolic compounds can exert cellular protective effects by their antioxidant activity. A phenolic‐enriched maple syrup extract (MSX) was previously reported to show protective effects against AGEs‐ and MGO‐induced cytotoxicity in human colon cells but its skin protective effects remain unknown. The protective effects of MSX were evaluated against hydrogen peroxide (H2O2)‐ and MGO‐induced cytotoxicity in human keratinocytes (HaCaT cells). Cellular viability and antioxidant activity were evaluated by the luminescent cell viability CellTiter‐Glo assay and the reactive oxygen species (ROS) assay, respectively. A single‐cell gel electrophoresis (Comet assay) was used to measure the strand breaks in the DNA of HaCaT cells. MSX (at 50 μg/mL) ameliorated H2O2‐ and MGO‐induced cytotoxicity by increasing cell viability by 21.5% and 25.9%, respectively. MSX reduced H2O2‐ and MGO‐induced ROS production by 69.4% and 56.6%, respectively. MSX also reduced MGO‐induced DNA damage by 47.5%. MSX showed protective effects against H2O2‐ and MGO‐induced cytotoxicity in HaCaT cells supporting its potential for dermatological and/or cosmeceutical applications.