The essential micronutrient iron (Fe) limits phytoplankton growth when dissolved Fe (dFe) concentrations are too low to meet biological demands. However, many of the processes that remove, supply, or transform Fe are poorly constrained, which limits our ability to predict how ocean productivity responds to ongoing and future changes in climate. In recent years, isotopic signatures (δ56Fe) of Fe have increasingly been used to gain insight into the ocean Fe cycle, as distinct δ56Fe endmembers of external Fe sources and δ56Fe fractionation during processes such as Fe uptake by phytoplankton can leave a characteristic imprint on dFe signatures (δ56Fediss). However, given the relative novelty of these measurements, the temporal scale of δ56Fediss observations is limited. Thus, it is unclear how the changes in ocean physics and biogeochemistry associated with ongoing or future climate change will affect δ56Fediss on interannual to decadal timescales. To explore the response of δ56Fediss to such climate variability, we conducted a suite of experiments with a global ocean model with active δ56Fe cycling under two climate scenarios. The first scenario is based on an atmospheric reanalysis and includes recent climate variability (1958–2021), whereas the second comes from a historical and high-emissions climate change simulation to 2100. We find that under recent climatic conditions (1975–2021), interannual δ56Fediss variability is highest in the tropical Pacific due to circulation and productivity changes related to the El Niño–Southern Oscillation (ENSO), which alter both endmember and uptake fractionation effects on δ56Fediss by redistributing dFe from different external sources and shifting nutrient limitation patterns. While the tropical Pacific will remain a hotspot of δ56Fediss variability in the future, the most substantial end-of-century δ56Fediss changes will occur in the Southern Hemisphere at middle to high latitudes. These arise from uptake fractionation effects due to shifts in nutrient limitation. Based on these strong responses to climate variability, ongoing measurements of δ56Fediss may help diagnose changes in external Fe supply and ocean nutrient limitation.