To advance our understanding of the responses of tropical cyclones (TCs) to abrupt climate transitions, we investigate the variation of genesis potential and the underlying mechanisms during Marine Isotope Stage 3 (MIS 3) that is characterized by frequent millennial-scale oscillations, using a set of coupled model simulations. We illustrate that genesis potential mainly increases over the eastern North Pacific and South Pacific in the storm season during MIS 3 interstadial relative to preindustrial, whereas it decreases over the western North Pacific, North Atlantic, South Indian Ocean, and Australian coast. The relative importance of each genesis factor to genesis potential change varies across oceans. During the transition from warm interstadial to cold stadial induced by freshwater injection, TC genesis potential generally decreases in the Northern Hemisphere, while increases in the Southern Hemisphere. These changes are associated with asymmetric variations of genesis factors between Northern and Southern Hemisphere, which are further tied to the adjustment of large-scale environmental factors in response to the weakened Atlantic meridional overturning circulation. Additionally, TC genesis potential exhibits a regional “overshoot” phenomenon when the freshwater injection is terminated, manifested by an increase over the eastern North Pacific and North Atlantic and a decrease over the South Pacific, compared with the initial interstadial state. Our results may help improve our knowledge on past TC behaviors and shed lights on TC response to potential abrupt climate transitions in a warmer future.