With a growing concern over rapid Antarctic ice loss in recent years, the Amundsen Sea, one of the fastest-melting areas in Antarctica, currently becomes a hotspot for the Earth sciences in the context of its linkage to global climate. As a center of strong physical and biological coupling processes, polynyas of the Amundsen Sea could act as sentinels of changes in atmosphere–ice–ocean interactions, offering a unique perspective into its sensitivity to climate variability. Here, we present a new, multiproxy-based high-resolution sedimentary record from the Amundsen Sea polynya, which provides new insights into environmental conditions of the region over the last 350 years and their linkages to climatic factors. Our results show that the polynya witnessed step-wise environmental shifts in parallel with the phases and strength of large-scale climate patterns, i.e., the Southern Annular Mode (SAM) and El Niño–Southern Oscillation (ENSO). Notably, intersite correlation of on-shelf Circumpolar Deep Water (CDW) intrusion signals at different locals suggests that the CDW may have gained increased access to the shelves at the time of a strong coupling of positive SAM and El Niño states. We tentatively speculate that anomalous large-scale atmospheric and oceanic circulation patterns over the Southern Hemisphere, forced by increasing greenhouse gas levels, were strongly involved in the mid-20th century CDW invigoration, which may be greater in scale that goes well beyond the Amundsen Sea region. This result is relevant to the current debate on spatial heterogeneity in the timing and phasing of major climatic events in Antarctica, underscoring an unambiguous connection of the Antarctic climate state to the large-scale ocean–atmosphere reorganizations. Our study also extends a growing evidence that today's global warming trend is expected to have a severe effect on future configuration of Antarctic continental ice-shelf environment.