Major and trace element and radiogenic isotopic characteristics of primitive mafic Pleistocene and Holocene lavas from Newberry Volcano, Oregon, define two groups. The first consists of dry tholeiitic high-alumina olivine basalts that are slightly enriched in highly incompatible elements. The second group consists of calc-alkaline basalts that contained 2–4 wt % H₂O prior to eruption and shows strong enrichment in the light rare earth elements, Ba, and Sr, and deficits in Nb, Ta, Hf, and Zr. The tholeiitic basalts reflect 6–11% anhydrous adiabatic decompression melting of spinel peridotite. The calc-alkaline basalts derived from compositionally distinct sources with strong LIL enrichment and relative depletion in HFSE, but with Sr, Nd, Hf, and Pb isotopic composition only slightly distinct from the sources of the tholeiitic magmas. Radiogenic Os correlates with LREE enrichment in the calc-alkaline magmas, which indicates that their source materials include a contribution from a mafic component that was melted in the garnet stability field. The calc-alkaline magmas were derived by melting of peridotite metasomatized by a fluid/melt that originated by melting of a mixture of the sediment plus MORB basalt/mantle in the underlying subducting oceanic plate. While the trace element characteristics of the calc-alkaline magmas were determined by the subduction component, their isotopic characteristics were modified during transit through the mantle by interaction with the highly magmatically processed mantle wedge beneath Newberry Volcano that, without the slab component, serves as the source of the tholeiitic magmas.