Partial melting of Earth’s mantle generates oceanic crust and leaves behind a chemically depleted residual mantle. The time-integrated composition of this chemically depleted mantle is generally inferred from basalts produced at mid-ocean ridges. However, isotopic differences between oceanic mantle rocks and mid-ocean ridge basalts suggest that mantle and basalt composition could differ. Here we measure neodymium isotope ratios in olivine-hosted melt inclusions from lavas of the Azores mantle plume. We find neodymium isotope ratios that include the highest values measured in basalts, and suggest that melts from ultra-depleted mantle contribute to the isotopic diversity of the erupted lavas. Ultra-depleted melts have exceedingly low preservation potential during magma extraction and evolution due to progressive mixing with melts that are enriched in incompatible elements. A notable contribution of ultra-depleted melts to the Azores mantle plume therefore implies that variably depleted mantle is the volumetrically dominant component of the Azores plume. We argue that variably depleted mantle, sometimes ranging to ultra-depleted compositions, may be a ubiquitous part of most ocean island and mid-ocean ridge basalt sources. If so, Earth’s mantle may be more depleted than previously thought, which has important implications for the rate of mass exchange between crust and mantle, plume dynamics and compositional stratification of Earth’s mantle.