The Tibetan Plateau (TP) hosts more than one thousand lakes (>1km2) in its endorheic basins. The changing climate in recent decades has led to significant modifications in the endorheic hydrologic system. Most TP lakes experienced dramatically expanding areas, rising water levels, and increasing storage, which inevitably influenced the lake salinity. This study provides a regional-scale investigation of water salinity changes of the TP lakes (for 83 lakes with two-epoch salinity records, among the approximately 160 lakes >50km2) by synthesizing multi-source data around the 1970s and 2010s. Our results reveal lake salinity has considerably declined for most expanding lakes across the endorheic basins. The mean salinity of 62 terminal lakes dropped from 92.76 g l−1 to 42.00 g l−1 during the 1970s–2010s, in contrast to the slight variations (3.42 g l−1 to 1.48 g l−1) of the 21 exorheic or upstream lakes. As a result, many hypersaline lakes have become polysaline or oligosaline lakes, such as Cedo Caka, Norma Co, etc. In particular, some large lakes (e.g., Siling Co, ‘Twin Lakes’, and Ayakkum Lake) also experienced significant drops in water salinity, with the exceptional cases for Nam Co and Qinghai Lake probably due to the relatively low ratios of increased water mass to their net storages. The widespread declining water salinities could greatly influence bacterial richness, diversity, and evenness, and affect the aquatic carbon cycle and utilization in the high-altitude endorheic lakes. More attention should be paid on understanding the saline lake ecosystem evolution and the regional carbon cycle in response to changing water salinity of the TP lakes.