As a complex paleo-ocean located between the Tarim-North China and the Sibumasu/Baoshan blocks, the Proto-Tethys Ocean was opened from the rifting of the Supercontinent Rodinia and mainly closed at the end of the Early Paleozoic. The known studies suggest that there were many continents and/or micro-continents in the Proto-Tethys Ocean. During closure of the Proto-Tethys Ocean and assembly of these continents/micro-continents, some Early Paleozoic ophiolites and HP-UHP metamorphic rocks developed in East Asia similar to those Early Paleozoic orogens in Gondwana. However, some academic debates still remain on the boundaries of the Proto-Tethys Ocean and the nature, relationships and assembly processes of these continents/micro-continents to the Tarim-North China Continent to the north. These problems are important for revealing and reconstructing tectonic processes before the closure of the Proto-Tethys Ocean and the initial assembly of the Supercontinent Pangea. Not surprisingly, the Proto-Tethys tectonic domain is characterized by complex ocean-continent configurations, assemblies and dispersals of continents, from the rifting and drifting of the Supercontinent Rodinia to the assembly of the Supercontinent Pangea. Therefore, this paper mainly focuses on summarizing and discussing the northern part of the Proto-Tethys tectonic domain based on field geology, structural geology, magmatism, sedimentary formations, geochemical records, geochronology and tomography, in order to reveal three key aspects: 1) identifying the southern and northern boundaries of the Proto-Tethys Ocean; 2) establishing affinities of continents/micro-continents within the Proto-Tethys Ocean and its ocean-continent configuration; and 3) clarifying the temporal sequence and styles of micro-continental assembly and the closure of the Proto-Tethys Ocean. Integrated analysis results show that to the north the region is bounded by the paleo-Luonan-Luanchuan Suture (or Kuanping Suture) and its extension to West Kunlun; the southern boundary is marked by the Longmu Co-Shuanghu-Changning-Menglian Suture. The Tarim-Alax-North China Block to the north of the Proto-Tethys Ocean had a southward subduction polarity and collided with Gondwana along the northern margin of Gondwana in the Early Devonian. The southern branch of the Proto-Tethys Ocean may be closed, making the Greater South China Block, including the northern Qiangtang, Ruoergai, Yangtze and Cathaysia, Bureya-Jiamusi and Indochina blocks, southward subduction and accretion to the northern margin of Gondwana in the Early Devonian. The results also show that the North China Block had no clear affinity to Gondwana, whereas the other continental/micro-continental blocks, such as the Yangtze, Cathaysia, Tarim, Qaidam, Alax, North Qinling, Qilian, Oulongbuluke, South Qiangtang, Lhasa, Lanping-Simao and Indochina all have an affinity to Gondwana in the earlier part of the Early Paleozoic. During the interval 480–400 Ma these series of continental blocks/micro-continental blocks experienced gradual southward subduction and accretion to the eastern segment of the northern margin of Gondwana, resulting in the closure of the Proto-Tethys Ocean and formation of the supercontinent called Proto-Pangea. The Greater South China Block and the Tarim-North China Block separated and drifted from Greater Gondwana of the Supercontinent Proto-Pangea since 380 Ma, resulting in the formation of the Paleo-Tethys and the Mianlue oceanic crusts. After this minor adjustment and until 240–220 Ma, they assembled northward gradually to develop Laurasia, which in turn resulted in the final formation of the Supercontinent Pangea.