The CO tuff is one of the volumetrically largest volcaniclastic events so far recorded in the Early-Middle Miocene Santa Cruz Formation (Patagonian Argentina). It represents aeolian processes, related with westerlies, that reworked and transported enormous quantities of volcanic ash from the Andes into the continental interior that accumulated in fluvial floodplain deposits. This volcanic event generated a major environmental change at ∼17 Ma (Burdigalian) and hostile living conditions for the biota of the area, at least during the time of deposition. We performed here a comprehensive study including taxonomic, sedimentological, and taphonomic aspects of the mammal assemblage recovered from this tuff deposit. The assemblage is constituted by representatives of Microbiotheria, Paucituberculata, Folivora, Cingulata, Rodentia, Notoungulata, and Litopterna, reflecting a wide mammalian diversity. The formation of the assemblage can be linked to a normal attritional model, in which the death of the individuals and subsequent deposition and burial of their remains would have occurred gradually over time, simultaneously with the accumulation of volcanic ash, at the place of death or very close to it. The time between the death and burial would have been relatively short, in accordance with the rapid and continuous influx of volcanic ash to the depositional environment. This multidisciplinary study allows us to interpret and reconstruct the possible taphonomic pathways of the mammal assemblage and to provide novel information on this particular preservation context linked to volcanically-influenced fluvial environments.