Oxazole has critical roles not only in heterocycle (bio)chemistry research, but also as the backbone of many active natural and medicinal species. These diverse and specialised functions can be attributed to the unique physicochemical properties of oxazole. This contribution investigates the reaction of oxazole and its derivatives with singlet oxygen, employing density functional theory DFT-B3LYP calculations. The absence of allylic hydrogen in oxazole eliminates the ene-mode addition of singlet oxygen to the aromatic ring. Therefore, the primary reaction pathway constitutes the [4 + 2]-cycloaddition of singlet oxygen to oxazole ring, favouring an energetically accessible corridor of 57 kJ/mol to produce imino-anhydride which is postulated to convert to triamide end-product in subsequent steps. The pseudo-first-order reaction rate for substituted oxazole (e.g., 4-methyl-2,5-diphenyloxazole, 1.14 × 106 M−1 s−1) appears slightly higher than that of unsubstituted oxazole (0.94 × 106 M−1 s−1) considering the same initial concentration of the species at 300 K, due to the electronic effect of the functional groups. The global reactivity descriptors have justified the relative influence of the functional groups along with their respective physiochemical properties.