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Bosten Lake, the largest inland freshwater lake in China, has experienced drastic change over the past five decades. Based on the lake water balance model and climate elasticity method, we identify annual changes in the lake’s water components during 1961-2016 and investigate its water balance. We find a complex pattern in the lake’s water: a decrease (1961-1987), a rapid increase (1988-2002), a drastic decrease (2003-2012), and a recent drastic increase (2013-2016). We also estimated the lake’s water balance, finding that the drastic changes are caused by a climate-driven regime shift coupled with human disturbance. The changes in the lake accelerated after 1987, which may have been driven by regional climate wetting. During 2003 to 2012, implementation of the ecological water conveyance project (EWCP) significantly increased the lake’s outflow, while a decreased precipitation led to an increased drought frequency. The glacier retreating trend accelerated by warming, and caused large variations in the observed lake’s changes in recent years. Furthermore, wastewater emissions may give rise to water degradation, human activity is completely changing the natural water cycle system in the Bosten Lake. Indeed, the future of Bosten Lake is largely dependent on mankind.