The amalgamation of the Central Asian Orogenic Belt in the southwestern Tian Shan in Tajikistan is represented by tectono-magmatic-metamorphic processes that accompanied late Paleozoic ocean closure and collision between the Karakum-Tarim and Kazakh-Kyrgyz terranes. Integrated U-Pb geochronology, thermobarometry, pseudosection modeling, and Hf geochemistry constrain the timing and petro-tectonic nature of these processes. The Gissar batholith and the Garm massif represent an eastward, along-strike increase in paleodepth from upper-batholith (~21–7 km) to arc-root (~36–19 km) levels of the Andean–syn-collisional Gissar arc, which developed from ~323–288 Ma in two stages: (i) Andean, I-type granitoid magmatism from ~323–306 Ma due to northward subduction of the Gissar back-arc ocean basin under the Gissar microcontinent, which was immediately followed by (ii) syn-collisional, I-S-type granitoid magmatism in the Gissar batholith and the Garm massif from ~304–288 Ma due to northward subduction/underthrusting of Karakum marginal-continental crust under the Gissar microcontinent. A rapid isotopic pull-up from ~288–286 Ma signals the onset of juvenile, alkaline-syenitic, post-collisional magmatism by ~280 Ma, which was driven by delamination of the Gissar arclogite root and consequent convective asthenospheric upwelling. Whereas M–HT/LP prograde metamorphism in the Garm massif (650–750°C/6–7 kbar) from ~310–288 Ma was associated with subduction-magma inundation and crustal thickening, HT/LP heating and decompression to peak-metamorphic temperatures (~800–820°C/6–4 kbar) at ~288 ± 6 Ma was driven by the transmission of a post-collisional, mantle-derived heat wave through the Garm-massif crust.