The Neo-Tethys Ocean was an eastward-gaping triangular oceanic embayment between Laurasia to the north and Gondwana to the south. The Neo-Tethys Ocean was initiated from the Early Permian with mircoblocks rifted from the northern margin of Gondwana. As the microblocks drifted northwards, the Neo-Tethys Ocean was expanded. Most of these microblocks collided with the Eurasia continent in the Late Triassic, leading to the final closure of the Paleo-Tethys Ocean, followed by oceanic subduction of the Neo-Tethys oceanic slab beneath the newly formed southern margin of the Eurasia continent. As the splitting of Gondwana continued, African-Arabian, Indian and Australian continents were separated from Gondwana and moved northwards at different rates. Collision of these blocks with the Eurasia continent occurred at different time during the Cenozoic, resulting in the closure of the Neo-Tethys Ocean and building of the most significant Alps-Zagros-Himalaya orogenic belt on Earth. The tectonic evolution of the Neo-Tethys Ocean shows different characteristics from west to east: Multi-oceanic basins expansion, bidirectional subduction and microblocks collision dominate in the Mediterranean region; northward oceanic subduction and diachronous continental collision along the Zagros suture occur in the Middle East; the Tibet and Southeast Asia are characterized by multi-block riftings from Gondwana and multi-stage collisions with the Eurasia continent. The negative buoyancy of subducting oceanic slabs can be considered as the main engine for northward drifting of Gondwana-derived blocks and subduction of the Neo-Tethys Ocean. Meanwhile, mantle convection and counterclockwise rotation of Gondwana-derived blocks and the Gondwana continent around an Euler pole in West Africa in non-free boundary conditions also controlled the evolution of the Neo-Tethys Ocean.