The accreted Talkeetna arc, south-central Alaska, is an archetypal example of an intra-oceanic arc crustal section. Arc-related units include all levels of a lithospheric column, from residual mantle harzburgites to sub-aerial volcanic rocks, and provide a rare opportunity to study intrusive arc processes directly. We present the first high-precision U-Pb zircon ages and an extensive new data set of 143Nd/144Nd and 87Sr/86Sr isotopic analyses from Talkeetna arc plutonic rocks. These data provide new insight into the timing and extent of Talkeetna arc magmatism, the tectonic development of the arc, and the role of preexisting crustal material in the generation of arc magmas. New analyses from the exposed arc crustal section in the Chugach Mountains indicate that the Talkeetna arc began to develop as a juvenile [ϵNd(t) = 6.0–7.8 and 87Sr/86Srint = 0.703379–0.703951] intra-oceanic arc between 202.1 and 181.4 Ma. This initial arc plutonism was followed ca. 180 Ma by a northward shift in the arc magmatic axis and generation of a large plutonic suite in the Talkeetna Mountains. Plutons from the eastern Talkeetna Mountains yield U-Pb zircon ages of 177.5–168.9 Ma and are isotopically similar to the Chugach Mountains intrusions [ϵNd(t) = 5.6–7.2 and 87Sr/86Srint = 0.703383–0.703624]. However, plutons from the western Talkeetna Mountains batholith have more evolved initial isotopic ratios [ϵNd(t) = 4.0–5.5 and 87Sr/86Srint = 0.703656–0.706252] and contain inherited xenocrystic Carboniferous–Triassic zircons. These data are interpreted to represent assimilation of adjacent Wrangellia crust into arc magmas and require amalgamation of the Talkeetna arc with the Wrangellia terrane by ca. 153 Ma. As a whole, the combined U-Pb zircon and isotopic data from the Chugach and Talkeetna Mountains indicate that the main volume of Talkeetna arc magmas formed with little or no involvement of preexisting crustal material. These observations justify the use of the Talkeetna arc as a type section for intrusive intra-oceanic arc crust.