Modern marine settings are experiencing rapid deoxygenation mainly forced by global warming and anthropogenic eutrophication. Therefore, studies that assess the role of climate variability in large spatiotemporal deoxygenations during past climate changes are needed to better comprehend the consequences of the current global warming and ocean deoxygenation. In this respect, deep marine sediments associated to past oxic-to-anoxic transitions are useful palaeoarchives for understanding the interplay between climate variability, deep-water dynamics and large-scale deoxygenation. Moreover, they can offer long-term perspectives to modern marine settings that are suffering oxygen depletion due to climate change and anthropogenic pressure. In particular, sapropel layers from the Middle Pleistocene to the Holocene are excellent palaeoarchives of past large-scale deoxygenation events, since (i) they occurred during a similar Mediterranean hydrogeographic configuration to the present, (ii) have a robust chronological control, and (iii) previous studies have reconstructed the climate conditions that ruled during their deposition. In this work, we have applied empirical palaeoceanographic conceptual models to five sapropels (S1, S5, S6, S7 and S8) in three Eastern Mediterranean (EM) settings. The models suggest that the hydrographic regimes of all studied sapropels can be considered as analogues to those observed in certain modern marine restricted settings. The results obtained support the idea that climate and the degree of surface-water freshening are the primary factors that influence deep-water dynamics in marine restricted settings, that in turn control the frequency and intensity of bottom-water deoxygenation and the stability and depth of the chemocline. The deepest EM sites are the most vulnerable locations to develop bottom-water restriction and deoxygenation. Local hydrogeographic factors play an essential role in the extent and frequency of bottom-water deoxygenation. Particulate shuttling was very intense during sapropel deposition and water-mass exchange between EM and Western Mediterranean controlled the intensity of the basin reservoir effect and Mo budget in EM.