As a low-gradient arid region spanning the tropics to the temperate zone, the Lake Eyre basin has undergone gentle late Cenozoic crustal warping leading to substantial alluvial deposition, thereby forming repositories of evidence for palaeoclimatic and palaeohydrological changes from the Late Tertiary to the Holocene. Auger holes and bank exposures at five locations along the lower 500 km of Cooper Creek, a major contributor to Lake Eyre in the eastern part of the basin, yielded 85 luminescence dates (TL and OSL) that, combined wit a further 142 luminescence dates from northeastern Australia, have established a chronology of multiple episodes of enhanced flow regime from about 750 ka to the Holocene. Mean bankfull discharges on Cooper Creek upstream of the Innamincka Dome at 250–230 ka or oxygen isotope stages (OIS) 7–6 are estimated to have been 5 to 7 times larger than those of today, however, substantially less reworking has occurred during and after OIS 5 than before. Lower Cooper Creek appears to have similarly declined. In the Tirari Desert adjacent to Lake Eyre there is evidence of widespread alluvial activity, perhaps during but certainly before the Middle Pleistocene, yet the river became laterally restricted in OIS 7 to 5. While the Quaternary has been characterised by a dramatically oscillating wet–dry climate, since oxygen isotope stage OIS 7 or 6 there has been a general decline in the magnitude of the episodes of wetness to which the eastern part of central Australia has periodically returned. During the last full glacial cycle, Cooper Creek's periods of greatest runoff and sand transport were not during the last interglacial maximum of OIS 5e (132–122 ka) but later in OIS 5 when sea levels and global temperatures were substantially below those of 5e or today. Fluvial activity returned in OIS 4 and 3, but not to the extent of mid and late OIS 5; strongly seasonal but still powerful flows transported sand and fed source-bordering dunes in OIS 5 and 3. This chronology of fluvial activity in the late Quaternary broadly coincides with that for rivers of southeastern Australia and suggests that the wet phases in eastern central Australia have not been governed as much by the northern monsoon as by conditions in the western Pacific close to the east coast both north and south. Flow confinement within the Innamincka Dome has locally amplified Cooper Creek's energy, and here evidence exists for short but high-magnitude episodes of flow during the Last Glacial Maximum and in the early to middle Holocene, conditions that were capable of forming large palaeochannels but that were not long-lived enough to rework the river's extensive floodplains elsewhere along its length.