Revealing hydrologic variations in the past is helpful to understand the dynamic changes and evolution of a given water body. The widespread long-lived spruce forests growing in the mountainous area around Issyk Lake in Central Asia provide a good opportunity for dendrohydrologic studies about that lake. A regional tree-ring width chronology developed for Picea schrenkiana was used to reconstruct 345-year annual runoff for Issyk Lake. Based on frequency of the wettest/driest years and decades, the 20th century was identified as having the most frequent hydrologic fluctuations among the last three centuries. After applying a 21-year moving average, seven wet and six dry periods were found in the runoff reconstruction. The 10- and 2.1–5.4-year cycles of this reconstruction revealed that annual runoff variability of Issyk Lake may be influenced by solar activity and the atmosphere–ocean system. Spatial correlation proves that the runoff reconstruction contains climatic signals representative of a large area, including the western Tien Shan Mountains and Junggar Basin. A comparison between the annual runoff reconstruction and other hydroclimatic reconstructions reveals similar variations, particularly in the high-frequency domain. The annual runoff reconstruction also accurately captures some flood/drought events noted in the meteorological records and hydroclimatic reconstructions of Central Asia.