The Himalayan Orogen is a typical continental collision orogenic belt that formed during India-Asia collision. The orogeny involved a transition in tectonic regime, which led to E-W–trending extension during the middle Miocene. At the same time, widespread post-collisional adakitic magmatism occurred in southern Tibet, particularly in the Lhasa Terrane, and these rocks provide a valuable record of the collisional geodynamic processes within the lithosphere. Few studies have focused on the middle Miocene adakitic rocks of the Himalayan Orogen, so further research is required to constrain their origin and geodynamics. This study presents new geochronological and geochemical data, including the whole rock Sr-Nd and zircon Hf isotopic compositions from the Mayum pluton in the Mayum-Gong Tso area, Northern Himalaya. Zircon U-Pb ages show that the Mayum granodiorite porphyries crystallized at 16.67 ± 0.14 Ma (mean square weighted deviation [MSWD] = 0.82, n = 29) and 16.68 ± 0.16 Ma (MSWD = 1.13, n = 28), indicating that they formed during the middle Miocene. The major and trace element characteristics are as follows: SiO2 = 65.79–67.31 wt%, Al2O3 = 15.28–16.00 wt%, MgO = 1.77–1.89 wt%, Y = 12.0–13.5 ppm, Yb = 0.11–0.99 ppm, Sr = 719–822 ppm, (La/Yb)N = 21.89–27.02, Sr/Y = 56.1–65.5, and the rocks have weak negative Eu anomalies (Eu/Eu* = 0.76–0.85), indicating that they are adakitic rocks and show high Sr-Ba granite affinity. The Mayum granodiorite porphyries have high K2O contents (3.42–3.65 wt%), Na2O (3.76–4.04 wt%), and K2O/Na2O ratios of 0.91–0.95, indicating a high-K calc-alkaline affinity. All samples are enriched in large-ion lithophile elements and depleted in high field strength elements. The initial 87Sr/86Sr ratios are 0.709262–0.709327 and εNd(t) values are −6.36 to −7.07, which correspond to two-stage Nd model ages [TDM2(Nd)] of 1405–1348 Ma. In situ zircon Lu-Hf isotopic compositions are variable, with 176Hf/177Hf ratios of 0.2823845–0.282824, εHf(t) values of −13.37 to +2.17, and two-stage Hf model ages [TDM2(Hf)] of 1704–841 Ma. These geochemical and Sr-Nd-Hf isotopic characteristics indicate that the Mayum granodiorite porphyries may be derived from partial melting of the subducted Indian thickened ancient mafic lower crust (∼92%) mixed with depleted mid-ocean ridge basalt mantle material input (∼8%) slightly. Crust-mantle interaction was induced by asthenospheric upwelling followed by the underplating of the Himalayan lower crust beneath Southern Tibet during the middle Miocene in response to significant changes in the geodynamics of the India-Asia collisional orogen. These deep geodynamic processes reflect the break-off or rollback of the subducted Indian continental slab, which caused asthenospheric upwelling, the input of juvenile heat, and the addition of depleted mantle material. This study indicates that the middle Miocene Himalayan adakitic rocks, which include the Miocene Yardoi two-mica granite, Gyangzê granite porphyry dike, Bendui two-mica granite, Langkazi enclave, Kuday dacitic dike, Lasa pluton, and Mayum pluton, form a belt of adakitic rocks in the Northern Himalaya to the south of the Indus-Tsangpo Suture Zone. These adakitic rocks have similar temporal and spatial distributions, geochemical features, and Sr-Nd isotopic compositions, indicating that their petrogenesis and geodynamic settings were similar. At that time there was widespread initiation of N-S–trending rifting, exhumation of central Himalayan eclogites, and large changes in the compositions of Himalayan leucogranites in the Himalayan Orogen. These can be attributed to significant changes in the characteristics of the subducted Indian continental lithosphere during the middle Miocene. The middle Miocene Himalayan adakitic rocks provide valuable insights into this transition in the tectonic regime and deep geodynamic processes.