Flavin cofactors are central to many biochemical transformations and are typically tightly bound as part of a catalytically active flavoenzyme. This work indicates that naturally occurring flavins can act as stand-alone catalysts to promote the oxidation of biosynthetically inspired heterocycles in aqueous buffers. Flavin activity was compared with that of oxidases important in non-ribosomal peptide synthesis, providing a rare direct comparison between the catalytic efficacy of flavins alone and in the context of a full flavoenzyme. This study suggests that such oxidases are likely to possess an active site base, as oxidase activity was greater than that of flavins alone, particularly for less acidic substrates. These findings offer perspective on the development of robust and catalytically effective, designed miniature flavoenzymes.