The Deki Amhare complex is located in central Eritrea, within the Arabian–Nubian Shield (ANS). It consists of an inner core of monzogranite porphyry and diorite enclaves (MMEs), surrounded outwardly by granodiorite and quartz diorite. The zircon U–Pb ages, whole-rock geochemistry, and Sr–Nd–Hf isotopic compositions of the Deki Amhare complex granitoids were used to discuss the Neoproterozoic tectonics of the ANS. The Late Tonian granodiorite and quartz diorite are metaluminous and calc-alkaline to slightly high-K calc-alkaline I-type plutons, with ages of 811.2 ± 4.8 Ma and 811.6 ± 5.7 Ma, respectively. They exhibit positive εHf(t) (7.6–9.5) and εNd(t) (3.9–4.7) values and relatively low (87Sr/86Sr)i ratios (0.70374–0.70463), indicating that they derived from the partial melting of a metasomatized mantle wedge during intra-oceanic subduction. The Ediacaran monzogranite porphyry and MMEs are subalkaline to alkaline A2-type granitoids with ages of 620.0 ± 4.3 Ma and 614.8 ± 3.9 Ma. These display positive εHf(t) (5.3–8.7) and εNd(t) (4.2–4.7) values, as well as low (87Sr/86Sr)i ratios (0.70310–0.70480), implying that they formed through crust–mantle magma mixing related to post-collisional slab break-off. Based on these data, three stages of regional tectonic evolution can be described: (1) from ~1200 Ma to ~875 Ma, the mafic oceanic crust was derived from depleted mantle during the opening of the Mozambique Ocean; (2) from ~875 Ma to ~630 Ma, intra-oceanic subduction and arc formation occurred with the development of I-type batholiths; and (3) from ~630 Ma to ~600 Ma, crustal and lithospheric reworking took place post-collision, leading to the formation of A2-type granitoids.