Calcifying phytoplankton play an important role in marine ecosystems and global biogeochemical cycles, affecting the transfer of both organic and inorganic carbon from the surface to the deep ocean. Coccolithophores are the most prominent members of this group, being well adapted to low-nutrients environments (e.g., subtropical gyres). Despite urgent concerns, their response to rising atmospheric carbon dioxide levels (pCO2) and ocean acidification is still poorly understood, and short-term experiments may not extrapolate into longer-term climatic adaptation. Current atmospheric pCO2 (~390 ppmv) is unprecedented since at least 3 million years ago (Ma), and levels projected for the next century were last seen more than 34 Ma. Hence, a deep-time perspective is needed to understand the long-term effects of high pCO2 on the biosphere. Here we combine a comprehensive fossil data set on coccolithophore cell size with a novel measure of ecological prominence: Summed Common Species Occurrence Rate (SCOR). The SCOR is decoupled from species richness, and captures changes in the extent to which coccolithophores were common and widespread, based on global occurrences in deep-sea sediments. The size and SCOR records are compared to state-of-the-art data on climatic and environmental changes from 50 to 5 Ma. We advance beyond simple correlations and trends to quantify the relative strength and directionality of information transfer among these records. Coccolithophores were globally more common and widespread, larger, and more heavily calcified in the pre-34 Ma greenhouse world, and declined along with pCO2 during the Oligocene (34–23 Ma). Our results suggest that atmospheric pCO2 has exerted an important long-term control on coccolithophores, directly through its availability for photosynthesis or indirectly via weathering supply of resources for growth and calcification.