Global change induced regional environmental variation and related catastrophic surface processes have greatly affected human life and social development during the last decades. These occurrences have also been highlighted by pre-historical catastrophes exposed by archaeological excavation in the Lajia Ruins at the northeast margin of the Tibetan Plateau, which has attracted considerable focus from both geologists and the world media. The cause of the disasters responsible for the destruction of the Lajia Settlement (14C age 4.15–3.85 ka BP) of the Qijia Culture remains controversial due to insufficient investigation of the Holocene sedimentary succession needed to establish a complete pedo-stratigraphic sequence and chronology, and thus to precisely constrain environment variation and related surface processes at that time. During our field investigations, a complete and continuous Holocene soil and sediment profile was identified in the northern part of the Lajia Ruins uniquely. Soil and sediment samples were taken systematically for physical and chemical analysis and optically stimulated luminescence (OSL) dating after detailed field observations and descriptions. The results demonstrate that the pedo-stratigraphic sequence includes Malan loess (L1-1, >11.50 ka BP) and transitional loess (Lt, 11.50–8.50 ka BP) in the bottom, a composite palaeosol (S0, 8.50–3.10 ka BP) in the middle, and recent loess (L0, 3.10–1.50 ka BP) and modern soil (MS, 1.50–0 ka BP) in the top. This pedo-stratigraphic sequence is comparable to those identified in the central part of the Loess Plateau. However, the mid-Holocene palaeosol (S0) is inserted by three layers of red clay (RC1, RC2, and RC3) and flashflood deposit (FFD), and thus subdivided into four sub-layers (S0-upper, S0-upper middle, S0-lower middle, and S0-lower). The red clays and the flashflood deposit are inferred to represent abrupt events of flashflood and mudflow that were dated to 3.96–3.65 ka by OSL and to 3.85–3.60 ka BP by AMS 14C methods. Indeed, the entire settlement, dwellings, pottery artifacts, and human skeletons in the Lajia Ruins are directly packed by these deposits. The Lajia Ruins is thus considered to be destroyed by enormous flashfloods and mudflows coming from the Ganggou and Lüjiagou gullies, which submerged the settlement at 14C 3.85 ka BP or OSL 3.96 ka. These disastrous events are related to climatic deterioration since 4.20 ka BP that has resulted in severe convective weather and strong rainstorms affecting the northeast margin of the Tibetan Plateau. With consideration of the badly deformed ground and dwelling floors in the Lajia Ruins by crisscrossing earthquake fissures, that are also infilled and packed by flashflood and mudflow deposits, it is concluded that great earthquakes occurred as the first hitting to the settlement at Lajia. The enormous flashfloods and mudflows may have been induced by multiple earthquakes and rainstorms simultaneously. These results bear important implications for a better understanding of pre-historic environmental change and human-land relationship evolution at the northeast margin of the Tibetan Plateau.