The poor hydrophilia and strong cytotoxicity of α-mangostin, a major component of xanthones from pericarps of mangosteen (Garcinia Mangostana L.), restrict its application in functional food. To overcome its shortage, a series of alginate/xanthan gum or alginate/κ-carrageenan hydrogels loaded with α-mangostin were fabricated and their anti-inflammatory effects were investigated under gastrointestinal tract (GIT). With the increased concentration of polysaccharides, the release of α-mangostin was slower due to denser microstructure and hardness. The digestive profile suggested that the release of α-mangostin in 0.3% alginate/0.15% xanthan gum (0.15%X-αM), 0.3% alginate/0.2% xanthan gum (0.25%X-αM) and 0.3% alginate/0.3% κ-carrageenan (0.3%C-αM) hydrogels were faster than the others. The cytotoxicity of α-mangostin loaded in hydrogels was dramatically reduced. However, the anti-inflammatory effect of the three intestinal digestive fluids was still maintained at 71.9% ± 1.2%, 83.1% ± 2.0%, and 70.6% ± 3.3% in LPS-induced Raw246.7 cells. In addition, the three intestinal digestive fluids (50 μM of α-mangostin) showed good inhibition of inflammatory cytokines (TNF-α, IL-6, and IL-1β) and the expression of iNos and Cox-2 respectively. Given these data, xanthan gum/κ-carrageenan-alginate composite hydrogels can be a good colonic target delivery system for bioactive compounds, which can be applied in functional foods to improve human health and wellness.