We study sediment cores retrieved during International Ocean Discovery Program (IODP) Expedition 385 to gain a deeper understanding of the Guaymas Basin's (GB) response to climate fluctuations over the past 22,400 years by analyzing coccolithophore assemblages and estimating net primary productivity (NPP). Coccolithophore-based data and the NPP at IODP Hole 1549 A reveal that the GB consistently remained an area of high productivity throughout the studied time interval, with an average productivity value of 1288.25 mgC m−2 day−1, with a gradually declining trend towards the present. Three main intervals are defined: (I) Cold, high productivity and vertically mixed surface waters during the Last Glacial Maximum and Heinrich Event 1 (22,400–15,320 cal yr BP), suggested by elevated net primary productivity (NPP), high abundance of Gephyrocapsa oceanica, and the presence of Coccolithus pelagicus subsp. braarudii. These conditions may be related to the incursion of the California Current Water into the GB. (II) Intermittent stratification with a deep position of the nutricline and thermocline during Bølling-Allerød, Younger Dryas, and broadly, the beginning of the Holocene (15,320–11,200 cal yr BP) indicated by an increase in relative abundance of Florisphaera profunda and the decrease in key coccolithophore taxa (notably G. oceanica and C. pelagicus subsp. braarudii). (III) Recurrent events of low productivity, warm surface water conditions with stratification since the beginning of the Holocene Climatic Optimum (11,200 cal yr BP-present), as suggested by the dominance of warm and oligo-mesotrophic water taxa (Helicosphaera spp., Calcidiscus leptoporus, Syracosphaera spp. and Umbilicosphaera sibogae) alongside a rise in F. profunda. From approximately 4900 cal yr BP to the present sustained stratification and declining NPP suggest the onset and intensification of modern monsoonal dynamics in the GB.