The so-called Big Five mass extinctions of the Phanerozoic include two prominent Palaeozoic episodes: the end-Ordovician and end-Permian events, both with large biodiversity loss. We consider that the end-Ordovician (Hirnantian) extinction could be best compared to the Middle Permian end-Guadalupian (=Capitanian) extinction, rather than to the end-Permian (Permo-Triassic boundary; PTB) extinction. The end-Guadalupian extinction, ca. 8 Myr before the PTB extinction, occurred as an independent episode under extremely unique global setting with the lowest sea level and lowest Sr isotopic ratios in seawater of the Phanerozoic. Multiple similarities exist between the end-Ordovician (Hirnantian) and the end-Guadalupian (Capitanian) events, such as the preferential elimination of sessile biota in the tropics, a global sea-level drop and secular changes in seawater C and Sr isotope ratios, occurring under global cooling. The limited development of land vegetation suggests that the Ordovician extinction was restricted solely to the marine realm, with no prominent damages on land, and no large igneous province (LIP) recognized in the Ordovician. The comparison indicates that the two extinctions of the Hirnantian and of the Capitanian have been essentially triggered by similar causes/processes; nonetheless, biotic responses were different, owing to the more oxygenated status of surface environments in the Permian after the mid-Palaeozoic terrestrialization.