Two sediment sequences from Big Kyzykul Lake and the Shushenskoe paleolake in the Minusinsk depression, Southern Siberia, were studied by pollen, microfossil, and geochemical analyses, as well as radiocarbon dating. The records indicate the persistence of an arid period between ∼11.7–7.6 cal kyr BP, increased effective moisture since ∼7.6 cal kyr BP, 2 humid impulses at ∼5.1 and 2.8 cal kyr BP separated by a dry interval, and the return to generally drier conditions after ∼1.5 cal kyr BP. This is contrary to the findings noted for the Eurasian temperate zone, but agrees with proxy data reported for arid and semi-arid zones of Central Asia. Reconstructed changes in climate and environment are in good agreement with archaeological data. Almost no evidence of the Mesolithic-Neolithic cultures has been reported for the depression, which is consistent with a dry early and mid-Holocene. Effective moisture started to rise from ∼7.6 cal kyr BP, followed by the beginning of human occupation at ∼6 cal kyr BP. Two maxima of humidity are recorded in the late Holocene, corresponding to the arrival of trees in the depression. No gap was to be found from the Early Bronze to the Iron ages cultures at this time, with the exception of a dry interval at ∼3.6–3.3 cal kyr BP, when the Minusinsk depression was sparsely occupied. The data obtained suggest a close relationship between climate change and cultural dynamics in the steppe zone of Southern Siberia.