Current understanding of global temperature and sea-level change over the Plio-Pleistocene remains poorly constrained and highly uncertain. We address these issues by reconstructing regional and global temperature evolution using ~120 published SST records that span some to all of the last 4.5 Myr. We use the resulting globally averaged SST difference to derive differences in global mean surface temperature and mean ocean temperature. We subtract reconstructed changes in mean ocean temperature from a global benthic oxygen isotope stack to derive the oxygen isotopic composition of seawater. We then reconstruct global mean sea level from our seawater isotope record by accounting for temperature effects on the isotopic composition of the main global ice sheets. Our reconstructions suggest that global cooling between 4.0-0.8 Ma was accompanied by intensification of Northern Hemisphere glaciation by 2.5 Ma, with subsequent fluctuations of large, LGM-like ice sheets occurring under a range of temperatures and temperature variability. These results present fundamental challenges to our understanding of ice sheet-climate interactions, including controls on ice-sheet inception and growth, and require a reassessment of hypotheses for the middle Pleistocene transition that invoke an increase in ice-sheet volume.