Uppermost Palaeozoic and Mesozoic sediments from the Vardar suture zone in northern Greece record a cycle of Neotethyan oceanic basin opening and closure and their analysis places tight constraints on the geotectonic evolution of the area. The oldest post-Carboniferous sedimentary unit in the study area is the Examili Formation, which comprises mainly metaarkoses and metaquartzites, and was deposited in an intracontinental rift-related sedimentary basin in proximity to the Vertiskos Terrane during the Permian–Triassic. The Melissochori Formation (former Svoula flysch) comprises predominantly metasandstones with significant carbonate content and was deposited in front of a Carboniferous–Permian basement unit of volcanic-arc origin with minor input from older basement rocks, probably at the slope of a carbonate platform in the Early–Middle Jurassic. By contrast, the petrography and whole-rock geochemistry of sedimentary rocks of the Prinochori Formation point to a source area dominated by mafic–ultramafic but also intermediate rocks, presumably ophiolites and granodiorites or equivalents. This is reinforced by the presence of detrital chrome spinel, which is the first find of this mineral in sedimentary successions from the eastern Vardar Zone of northern Greece. Microprobe analyses suggest that most of the detrital chrome spinels were derived from MOR-type peridotites and supra-subduction zone (SSZ) peridotites, whereas only a small fraction comes from volcanic rocks, presumably mid-ocean ridge and island-arc basalts. The Prinochori Formation was probably deposited in front of a nappe complex in the Early Cretaceous, comprising ophiolitic rocks and basement slivers from the Vertiskos Terrane or equivalent rocks. Furthermore, a microfauna assemblage of Ovalveolina sp., Pseudonummuloculina sp. and dasycladacea algae of genus Thaumatoporella sp. was found in a calcareous clastic succession cropping out in the Oreokastro area, which was so far thought to be of Late Triassic–Middle Jurassic age. These data clearly indicate an Albian–Cenomanian age of deposition for this sedimentary succession. In conclusion, the rocks of the eastern Vardar suture zone record Mesozoic rifting, related to the opening of a Neotethyan Ocean, Middle Jurassic intraoceanic subduction, attendant volcanic-arc magmatism, ophiolite emplacement, and finally oceanic basin closure. Polyphase tectonics and metamorphism complicate palinspastic reconstructions.