The modern Gulf of Alaska (GOA) is a Cordilleran Ice Sheet (CIS) region, estimated to be important for nutrient cycling and CO2 exchange. Little is known of the GOA evolution over the Pliocene and Pleistocene as well as its impact on the CIS development, when other evidence for changing North Pacific circulation has emerged. We analyzed Integrated Ocean Drilling Program Expedition 341 Site U1417 sediments, which extend through the Plio-Pleistocene transition (4–1.7 Ma), focusing on productivity-related biomarkers (alkenones, brassicasterol), siliceous microfossils and bulk carbon and nitrogen stable isotopes. Our results show two dominant water column regimes: one characterized by high silica and low organic matter (OM) preservation, containing microorganism remains from a mix of habitats (4–3.7 Ma) and a second characterized by low biogenic silica and increased OM preservation of microorganisms from dominantly open ocean habitats (3.33–3.32 Ma and 2.8–1.66 Ma). An increase of phytoplankton diversity (3.7–3.35 Ma, 3.19–2.82 Ma) characterizes the two transitions of water column conditions, from oxygenated to reductive, that we attribute to a change from ocean mixing to strong stratified conditions with some occasional mixing. The biogeochemical changes in the GOA follow 400 and 100 kyr eccentricity cycles which are also reflected in changes in the CIS. We conclude that the CIS expansion created high nutrient low chlorophyll conditions in the GOA during the Mid Piacenzian Warm Period and the early Pleistocene. In turn, positive feedbacks increased marine productivity export, atmospheric CO2 drawdown and further CIS expansion.