The thermal degradation of the anthocyanins and antioxidant activity in purple maize extracts was determined between 80 and 180 °C. The anthocyanins were found to be thermostable in the temperature range of 80 to 120 °C, whereas at higher temperatures the thermal degradation of both anthocyanins and antioxidant activity followed a first-order kinetic model. The -values started from 61.72 ± 2.28 °C for anthocyanins and 75.75 ± 2.87 °C for antioxidant activity. The conformational space of pairs of model anthocyanin molecules at 25 and 180 °C was explored through a molecular dynamics test, and results indicated the occurrence of intermolecular self-association reactions and intramolecular co-pigmentation events, which might help explaining the findings of the degradation kinetics. The relationship between thermal degradation of anthocyanins and antioxidant activity and the in vitro release was further studied. The unheated extracts showed a high stability under gastric environment, whereas after heating at 180 °C, the digestion ended quickly after 60 min. After simulated intestinal digestion, the anthocyanins were slowly decreased to a maximum of 12% for the unheated extracts, whereas an 83% decrease was found after preliminary heating at 180 °C. The thermal degradation of anthocyanins was positively correlated with the in vitro decrease of antioxidant activity.