Fluctuations in the Pacific Walker Circulation (PWC), a zonally oriented overturning cell across the tropical Pacific, can cause widespread climatic and biogeochemical perturbations. It remains unknown how the PWC developed during the Cenozoic era, with its substantial changes in greenhouse gases and continental positions. Through a suite of coupled model simulations on tectonic timescales, we demonstrate that the PWC was ∼38° broader and ∼5% more intense during the Early Eocene relative to present. As the climate cooled from the Early Eocene to the Late Miocene, the width of the PWC shrank, accompanied by an increase in intensity that was tied to the enhanced Pacific zonal temperature gradient. However, the locations of the western and eastern branches behave differently from the Early Eocene to the Late Miocene, with the western edge remaining steady with time due to the relatively stable geography of the western tropical Pacific; the eastern edge migrates westward with time as the South American continent moves northwest. A transition occurs in the PWC between the Late Miocene and Late Pliocene, manifested by an eastward shift (both the western and eastern edges migrate eastward by <12°) and weakening (by ∼22%), which we show here is linked with the closure of the tropical seaways. Moreover, our results suggest that rising CO2 favors a weaker PWC under the same land-sea configurations, a robust feature across the large spread of Cenozoic climates considered here, supporting a weakening of the PWC in a warmer future.