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The formation of the Isthmus of Panama closed the Central American Seaway, severing the only Late Cenozoic low‐latitude connection between the Pacific and Atlantic Oceans. Here we clarify the Early Pliocene (5.3–3.6 million years ago [Ma]) sequence of events associated with the shoaling of the Central American Seaway based on differences in upper ocean biogeochemical properties between the eastern tropical North Pacific (ETNP) and the Caribbean Sea. Foraminifera‐bound nitrogen isotopes (FB‐δ¹⁵N) are elevated in the ETNP relative to the Caribbean Sea throughout the Early Pliocene. Whereas ETNP FB‐δ¹⁵N shows no long‐term trend across the Early Pliocene, FB‐δ¹⁵N in the Caribbean Sea declines by ∼0.5‰ between 4.6 and 4.5 Ma, and by an additional ∼1‰ between 4.35 and 4.25 Ma. We interpret the divergence between ETNP and Caribbean Sea FB‐δ¹⁵N to indicate progressive isolation of their subsurface nutrient pools due to CAS shoaling. The oxygen isotopic composition of seawater (δ¹⁸O_sw) derived from planktonic foraminiferδ¹⁸O and Mg/Ca shows a small but variable gradient between the ETNP and Caribbean Sea over the Early Pliocene, with a trend toward a largerδ¹⁸O_swgradient after 4.25 Ma. We suggest that the development of persistent chemical differences in both thermocline nutrients and surface waters between the ETNP and Caribbean Sea after 4.1 Ma reflects the cessation of basin‐scale oceanic exchanges across the Central American Seaway. 

The impact of global warming on the ocean’s oxygen-deficient zones (ODZs) is uncertain, partly because of a lack of data on past changes. We report monthly resolved records of coral skeleton–bound nitrogen isotopes (CS-δ¹⁵N) to reconstruct denitrification in the Eastern Tropical North Pacific (ETNP) ODZ over the last 80 years. The data indicate strong decadal variation in ETNP denitrification, with maxima during the cool North Pacific phase of Pacific Decadal Variability. The maxima in denitrification (and thus oxygen deficiency) were likely due to stronger upwelling that enhanced productivity leading to greater oxygen demand in the thermocline. Prior findings of multidecadal-to-centennial ODZ trends were likely biased by this variability. ODZ evolution over the next century will depend on how global warming interacts with the decadal oscillations.