Achieving high stability is critical for the implementation of organic electrochemical transistors (OECTs) in more diverse and demanding applications. However, the sources and mechanisms of OECT degradation have not been rigorously explored. Here, we employ a variety of biasing schemes to separate the relative effects of oxidative bias stress, reductive bias stress, and current stress on degradation of thiophene-based, p-type OECTs. We find that accelerated degradation arises from the compounding effects of simultaneous oxidative and reductive bias stress and is common across several thiophene-based channel materials. To understand the underlying mechanism of OECT channel degradation, we explore the individual contributions of dissolved oxygen and source-drain electrode materials. We determine that the reaction of dissolved oxygen at the buried Au/OMIEC interface of the drain electrode experiencing reductive potentials produces a mobile reactive species that aggressively degrades the oxidized OMIEC throughout the device, destroying its conjugation and disrupting electronic charge transport. Importantly, we find that this mechanism can be disrupted by alternatively removing oxygen, avoiding reductive potentials in the device biasing scheme, replacing Au electrodes with a noncatalytic alternative, or passivating Au electrodes with self-assembled monolayers. These conclusions can inform both future standards of stability testing in the field as well as design considerations of OECT implementation in long-term applications.