Transglutaminase 2 (TG2) is an inducible transamidating acyltransferase that catalyzes Ca²⁺-dependent protein modifications. TG2 enzyme disruption has been implicated in several different disease processes and disorders such as Huntington and Parkinson’s diseases, and cancers such as breast, ovarian and pancreatic cancers. Coeliac disease (CD) is the one disease state which TG2 activity plays a crucial role. To date, a gluten-free diet is the only accepted form of therapy for CD. Because of the important role of TG2 enzyme in the initiation of CD, therefore, this study was aimed at the identification of TG2 inhibitors from natural sources, as a potential intervention in CD therapy. Competitive amine inhibitors are the most widely used TG2 inhibitors because they are commercially available, chemically stable and relatively non-toxic in living systems. The natural products chosen for this study were dietary flavonoids. Flavonoids were extracted from different food samples. The flavonoid food extracts were subjected to the TG2 activity assays to examine their effect on the enzyme activity. The assays were carried out under optimal conditions of pH, Ca²⁺ and with N, N-dimethylcasein (acyl-donor) or casein (acyl-acceptor) as acyl-donor substrates and biotin cadaverine (acyl-acceptor) or TVQQEL as (acyl-donor) substrates. TG activity was measured by two different microplate assays, a Biotin-labeled cadaverine incorporation assay and Biotin-labeled peptide cross-linking assay. In the TG2 amine incorporation activity, all of food extracts display a significant inhibition effect towards the human recombinant transglutaminase2 (hrTG2) and guinea pig transglutaminase 2 (gplTG2) (20%-50% of inhibition). While in the TG2 cross-linking activity, the majority of food extracts displayed an inhibition effect on the gplTG2 cross-linking activity (50%-70% inhibition) but only the strawberry and kale extracts showed an effect on hrTG2 activity (40%-50% inhibition). The inhibition of TG2 activity can be considered as a potential therapeutic target in the treatment of CD.