ABSTRACT Nitrogen-fixing (N ₂ ) cyanobacteria provide bioavailable nitrogen to vast ocean regions but are in turn limited by iron (Fe) and/or phosphorus (P), which may force them to employ alternative nitrogen acquisition strategies. The adaptive responses of nitrogen fixers to global-change drivers under nutrient-limited conditions could profoundly alter the current ocean nitrogen and carbon cycles. Here, we show that the globally important N ₂ fixer Trichodesmium fundamentally shifts nitrogen metabolism toward organic-nitrogen scavenging following long-term high-CO ₂ adaptation under iron and/or phosphorus (co)limitation. Global shifts in transcripts and proteins under high-CO ₂ /Fe-limited and/or P-limited conditions include decreases in the N ₂ -fixing nitrogenase enzyme, coupled with major increases in enzymes that oxidize trimethylamine (TMA). TMA is an abundant, biogeochemically important organic nitrogen compound that supports rapid Trichodesmium growth while inhibiting N ₂ fixation. In a future high-CO ₂ ocean, this whole-cell energetic reallocation toward organic nitrogen scavenging and away from N ₂ fixation may reduce new-nitrogen inputs by Trichodesmium while simultaneously depleting the scarce fixed-nitrogen supplies of nitrogen-limited open-ocean ecosystems. IMPORTANCE Trichodesmium is among the most biogeochemically significant microorganisms in the ocean, since it supplies up to 50% of the new nitrogen supporting open-ocean food webs. We used Trichodesmium cultures adapted to high-CO ₂ conditions for 7 years, followed by additional exposure to iron and/or phosphorus (co)limitation. We show that “future ocean” conditions of high CO ₂ and concurrent nutrient limitation(s) fundamentally shift nitrogen metabolism away from nitrogen fixation and instead toward upregulation of organic nitrogen-scavenging pathways. We show that the responses of Trichodesmium to projected future ocean conditions include decreases in the nitrogen-fixing nitrogenase enzymes coupled with major increases in enzymes that oxidize the abundant organic nitrogen source trimethylamine (TMA). Such a shift toward organic nitrogen uptake and away from nitrogen fixation may substantially reduce new-nitrogen inputs by Trichodesmium to the rest of the microbial community in the future high-CO ₂ ocean, with potential global implications for ocean carbon and nitrogen cycling.