The shoaling and final closure of the Central American Seaway (CAS) resulted in a major change of the global ocean circulation and has been suggested as an essential driver for strengthening of Atlantic Meridional Overturning Circulation (AMOC). The exact timing of CAS closure is key to interpreting its importance. Here we present a reconstruction of deep and intermediate water Nd and Pb isotope compositions obtained from fossil fish teeth and the authigenic coatings of planktonic foraminifera in the eastern equatorial Pacific (Ocean Drilling Program (ODP) Site 1241) and the Caribbean (ODP Sites 998, 999, and 1000) covering the final stages of CAS closure between 5.6 and 2.2 Ma. The data for the Pacific site indicate no significant Atlantic/Caribbean influence over this entire period. The Caribbean sites show a continuous trend to less radiogenic Nd isotope compositions during the Pliocene, consistent with an enhancement of Upper North Atlantic Deep Water (UNADW) inflow and a strengthening of the AMOC. Superimposed onto this long-term trend, shorter-term changes of intermediate Caribbean Nd isotope signatures approached more UNADW-like values during intervals when published reconstructions of seawater salinity suggested complete closure of the CAS. The data imply that significant deep water exchange with the Pacific essentially stopped by 7 Ma and that shallow exchange, which still occurred at least periodically until approximately 2.5 Ma, may have been linked to the strength of the AMOC but did not have any direct effect on the intermediate and deep Caribbean Nd isotope signatures through mixing with Pacific waters.