During the Middle Miocene, Earth’s climate transitioned from a relatively warm phase (Miocene climatic optimum) to a colder mode with reestablishment of permanent ice sheets on Antarctica, thus marking a fundamental step in Cenozoic cooling. Carbon sequestration and atmospheric CO2 drawdown through increased terrestrial and/or marine productivity have been proposed as the main drivers of this fundamental transition. We integrate high-resolution (1–3 k.y.) benthic stable isotope data with X-ray fluorescence scanner–derived biogenic silica and carbonate accumulation estimates in an exceptionally well preserved sedimentary archive, recovered at Integrated Ocean Drilling Program Site U1338, to reconstruct eastern equatorial Pacific productivity variations and to investigate temporal links between high- and low-latitude climate change over the interval 16–13 Ma. Our records show that the climatic optimum (16.8–14.7 Ma) was characterized by high-amplitude climate variations, marked by intense perturbations of the carbon cycle. Episodes of peak warmth at (Southern Hemisphere) insolation maxima coincided with transient shoaling of the carbonate compensation depth and enhanced carbonate dissolution in the deep ocean. A switch to obliquity-paced climate variability after 14.7 Ma concurred with a general improvement in carbonate preservation and the onset of stepwise global cooling, culminating with extensive ice growth over Antarctica ca. 13.8 Ma. We find that two massive increases in opal accumulation ca. 14.0 and ca. 13.8 Ma occurred just before and during the final and most prominent cooling step, supporting the hypothesis that enhanced siliceous productivity in the eastern equatorial Pacific contributed to CO2 drawdown.