Tectonically induced changes in oceanic seaways had profound effects on ocean circulation and global climate during the Neogene. The constriction of the Panama Seaway reached a critical threshold during the early Pliocene. Subsequently, between ~4-3 Ma, the constriction of the Indonesian Seaway impacted regional climate and might have accelerated the Northern Hemisphere Glaciation. We here present the Pliocene Pacific benthic stable carbon isotope record and carbonate dissolution indicator in combination with that from the Atlantic Deep Water to reconstruct gateway-related changes in ocean circulation. Our records indicate a significant change in deep ocean circulation at about 4.3 Ma, which is consistent with surface water salinity contrast between the Caribbean Sea and the Pacific and is confirmed by model simulations that indicate the strengthening of the Atlantic Meridional Overturning Circulation. Different from the Atlantic, our results indicate the heat transport northward in the Pacific was dampened by the closure of the Panama Seaway, corresponding to the weakened East Asian monsoon and cooling in the North Pacific, which preconditioned for the expansion of the Northern Hemisphere Glaciation.