Polyphenols participate in the Maillard reaction pathways scavenging α-dicarbonyl compounds (DCs) and contributing to the mitigation of carbonyl burden through dietary exposure/routes. The current study demonstrated the effectiveness of high-molecular-weight brewer's spent grain melanoidins (HMW-BSGM) in reacting with DCs in an in vitro model system. HMW-BSGM (4 mg/mL) quenched more than 95% of glyoxal and methylglyoxal, and more than 80% of 2,3-butanedione after a 7-day incubation at 37 °C. Among tested polyphenols, sinapic acid showed the highest trapping capacity with inhibition rates of 33.1, 49.1 and 49.3% for glyoxal, methylglyoxal and 2,3-butanedione because of hydroxyalkylation reaction as revealed by liquid chromatography high-resolution tandem mass spectrometry experiments. The formation of free fluorescent AGEs was substantially hindered (79.3%) by HMW-BSGM (4 mg/mL). These findings corroborate the hypothesis that the accumulation of polyphenols in melanoidins skeleton can hinder undesired effects and potentially harmful reactions involving α-dicarbonyl compounds.