Monascus vinegar melanoidins (LVM), the primary constituents of Monascus vinegar, were subjected to in vitro simulated gastrointestinal digestion to assess their digestibility and bioactivity. While LVM underwent partial degradation, its core melanoidin structure remained intact. Structural characterization and chemical analysis revealed that carbohydrates, proteins, and phenols within LVM were affected during digestion. Specifically, over two-thirds of free phenolics were degraded in the gastrointestinal tract, while nearly 60% of bound phenolics survived digestion. Protein and bound phenolic degradation predominantly occurred in the stomach, whereas free phenolic degradation was more pronounced in the small intestine. The bioaccessible fraction of LVM in the small intestine exhibited cytoprotective effects against reactive oxygen species (ROS)-induced oxidative damage in Caco-2 cells. This protection was attributed to the scavenging of superoxide in the mitochondria and an increase in intracellular superoxide dismutase (SOD) activity. Multiple components within LVM likely contributed to these effects. These findings highlight the potential of LVM as a functional active factor and provide a theoretical foundation for the development of novel functional foods and dietary additives.