A great deal of effort is now focused on reconstructing atmospheric CO2 during periods of lower polar ice volume to better constrain carbon cycling under conditions similar to those expected in the future. Here we reconstruct the past 1,460,000 years of atmospheric CO2 by taking advantage of the unique relationship between CO2 concentration and leaf wax δ13C value resulting from changes in the distribution of plant functional types in East India. We find that CO2 variability is tightly coupled with variability of global ice volume and deep-ocean circulation on glacial–interglacial timescales. However, unexpectedly, interglacial CO2 concentrations were lower before the mid-Pleistocene transition (MPT; 900,000 years ago) than after it, despite the smaller continental ice volume. In contrast, CO2 covaried continuously with deep-ocean carbon isotopes. A shift in the relative phase of CO2 and ice volume cycles occurred during the MPT. These findings suggest that deep-ocean circulation controlled the long-term CO2 trend, and the interaction between CO2, continental ice, and deep-ocean circulation was reorganized during the MPT.