Dihydrolipoamide dehydrogenase is a flavoenzyme that catalyzes the oxidation of dihydrolipoamide to lipoamide with the concomitant reduction of NAD+ to NADH. In vivo this enzyme is a subunit of the pyruvate, α- ketoglutarate, and glycine dehydrogenase complexes where it catalyzes the final reaction in a sequence of oxidative reactions. Of these, the pyruvate dehydrogenase complex is a well-known regulator of central metabolism located in mitochondria and its activity is dependent on many factors including intracellular NAD+ /NADH ratio which are sensed directly through the lipoamide dehydrogenase component. It has been established that dihydrolipoamide dehydrogenase becomes inactivated when catalyzing the reverse reaction in the absence of added NAD+ and that this inactivation is more prominent at low pH. The proposed mechanism behind the inactivation is an overly reduced four electron dead-end state that is traditionally shown to occur by excess NADH to NAD+ ratio. Here we analyze a host of kinetic datasets from human, rat, spinach, and E. coli, showing that all datasets can be fitted to a common kinetic mechanism that accounts for this unique pH and NAD+ dependent activation/inhibitory phenomenon. The kinetic mechanism that we have identified is rapid and random in the binding and dissociation of substrates and products and accounts for the possibility of either ternary or ping-pong type pathways. Overall, our mechanism reproduces observations of NAD+ dependent progress curve lags, pH and NAD+ dependent velocity profile shifts, and product inhibition patterns while maintaining equilibrium and thermodynamic cycle constraints.