The Murzuq Basin is one of the most petroliferous basins of North Africa. Its remote eastern flank has been largely ignored since early reconnaissance work in the 1950s and 1960s. This article presents new stratigraphic and sedimentological data on the Neoproterozoic through Devonian succession from the Mourizidie and Dor el Gussa regions. The Neoproterozoic to Cambrian Mourizidie and Hasawnah formations in the eastern part of the Mourizidie region dip to the east and north-east, resting directly on late Precambrian metasediments and granitoids. These strata record the initial progradation of sand-dominated braidplain systems upon peneplained Precambrian basement. Rhyolite clasts in the Hasawnah Formation may record tectonically driven uplift and unroofing in the southern Tibesti Massif or tectonomagmatic rejuvenation to the south of this massif. In the western part of the Mourizidie region, Late Ordovician through Silurian strata (Mamuniyat and Tanezzuft–Akakus formations) directly overlie late Precambrian metasediments and granitoids, and dip at a low angle towards the west into the Murzuq Basin. Elsewhere at the eastern Murzuq Basin flank, in Dor el Gussa, Late Ordovician glaciogenic sediments rest with angular unconformity upon shallow marine sandstones of Cambrian–Ordovician age. This angular unconformity may also occur in the Mourizidie region and indicates widespread tectonism, either as a result of a Middle–Late Ordovician orogenic event, far-field tectonism related to the opening of the Rheic Ocean along the northern margin of Gondwana or alternatively crustal depression associated with the growth of Late Ordovician ice sheets. Unconformity development was also probably associated with glacial incision. Following ice sheet retreat, isostatic rebound during deglaciation resulted in uplift of tens to hundreds of metres, locally removing all Cambrian and Ordovician formations. Rising sea levels in the Silurian led to deposition of the Tanezzuft Formation on Precambrian basement in the northwestern Mourizidie region.