Changes in global mean sea level (GMSL) during the late Cenozoic remain uncertain. We use a reconstruction of changes in δ18O of seawater to reconstruct GMSL since 4.5 million years ago (Ma) that accounts for temperature-driven changes in the δ18O of global ice sheets. Between 4.5 and 3 Ma, sea level highstands remained up to 20 m above present whereas the first lowstands below present suggest onset of Northern Hemisphere glaciation at 4 Ma. Intensification of global glaciation occurred from 3 Ma to 2.5 Ma, culminating in lowstands similar to the Last Glacial Maximum lowstand at 21,000 years ago and that reoccurred throughout much of the Pleistocene. We attribute the middle Pleistocene transition in ice sheet variability (1.2 Ma to 0.62 Ma) to modulation of 41-thousand-year (kyr) obliquity forcing by an increase in ~100-kyr CO2 variability.