Organic light-emitting devices (OLEDs) containing organic molecules that exhibit thermally activated delayed fluorescence (TADF) produce high efficiencies. One challenge to the commercialization of the TADF OLEDs that remains to be addressed is their operational stability. Here we investigate the molecular factors that govern the stability of various archetypal TADF molecules based on a cycloamino donor–acceptor platform. Our results reveal that the intrinsic stability depends sensitively on the identity of the cycloamino donors in the TADF compounds. The rates and photochemical quantum yields of the degradation are positively correlated with the operation lifetimes of the devices. Our research shows that the stability is governed by the conformeric heterogeneity between the pseudo-axial and pseudo-equatorial forms of the cycloamino donor. Spontaneous bond dissociation occurs in the former (i.e., the pseudo-axial form), but the cleavage is disfavored in the pseudo-equatorial form. These findings provide valuable insights into the design of stable TADF molecules.