We have analyzed four sediment cores from the Southern Indian Ocean (ODP sites 757, 758, 1135 and 762) with high carbonate content, in order to reconstruct the neodymium isotopic composition (εNd) of ancient intermediate South Indian seawater from Late Cretaceous (90 Ma) to Early Eocene (40 Ma). The εNdvariations are highly consistent and exhibit reproducible patterns over a very large geographic area, confirming the seawater origin of the signal. Combining geochemical constraints with paleogeographic reconstructions, we highlight the respective roles of (1) large-scale tectonic events, (2) continental weathering from surrounding Precambrian terrains (90–65 Ma), (3) oceanic circulation changes (50–40 Ma) and, possibly, (4) local volcanism of the ultra-fast spreading South East Indian Ridge (SEIR) (60–50 Ma) on the Nd isotopic composition of South Indian seawater. Between 60 Ma and 50 Ma, the regional Nd isotopic variations closely mimic changes in SEIR spreading rate. We suggest that the Nd isotopic composition of seawater could be influenced by Nd of volcanic origin in the vicinity of ultra-fast spreading ridges (>13 cm/yr). The India-Asia collision closed the Equatorial Seaway between Asia and India and drastically changed oceanic circulation patterns in the Indian Ocean: warm and more radiogenic Pacific equatorial seawater was diverted to the South by the East Indian coast. A stronger mixing of this Pacific seawater with South Indian seawater would explain the rapid shift ofεNd from 50 Ma (−11) to 40 Ma (−8).