Despite decades of research, the mechanisms and processes of subduction initiation remain obscure, including the tectonic settings where subduction initiation begins and how magmatism responds. The Cretaceous Mawgyi Volcanics represent the earliest volcanic succession in the Wuntho-Popa arc of western Myanmar. This volcanic unit consists of an exceptionally diverse range of contemporaneously magmatic compositions which are spatially juxtaposed. Our new geochemical data show that the Mawgyi Volcanics comprise massive mid-oceanic ridge basalt (MORB)-like lavas and dikes, and subordinate island arc tholeiite and calc-alkaline lavas. The Mawgyi MORB-like rocks exhibit flat rare earth elements (REEs) patterns and are depleted in REEs, high field strength elements (except for Th) and TiO2 concentrations relative to those of MORBs, resembling the Izu-Bonin-Mariana protoarc basalts. Our geochronological results indicate that the Mawgyi Volcanics formed between 105 and 93 Ma, coincident with formation of many Neotethyan supra-subduction zone ophiolites and intraoceanic arcs along orogenic strike in the eastern Mediterranean, Middle East, Pakistan, and Southeast Asia. Combined with its near-equatorial paleo-latitudes constrained by previous paleomagnetic data, the Wuntho-Popa arc is interpreted as a segment of the north-dipping trans-Neotethyan subduction system during the mid-Cretaceous. Importantly, our restoration with available data provides new evidence supporting the hypothesis of a mid-Cretaceous initiation of this >8000-km-long subduction system formed by inversion of the ∼E-W–trending Neotethyan oceanic spreading ridges, and that this was contemporaneous with the final breakup of Gondwana and an abrupt global plate reorganization.