Lake ecosystems in arid regions are highly sensitive to hydroclimatic triggers. Understanding the long-term trends of their ecological evolution and response to hydrological stressors is essential for future sustainability under global changes. In this study, we present a similar to 350-year ecological record of Lake Issyk-Kul, a large alpine lake in arid Central Asia, based on multi-biomarker signatures (n-alkanes, n-alkanoic acids, and alcohols) from a well-dated sediment core. High Paq (proportions of aquatic macrophytes) values and related proxies suggest that, between 1674 and 1840 CE, Lake Issyk-Kul was an open lake system with abundant submerged/floating macrophytes, attributed to high water levels. A significant ecological shift occurred during the 1770s-1840s, marked by a decline in submerged/floating macrophytes and increase in emergent plants, likely in response to excessive water-level fluctuations following the disconnection of the Chu River from the lake. Since the mid-19th century, the endorheic Lake Issyk-Kul has experienced a decline of over 10 m in water levels, which facilitated the expansion of macroalgae Chara, as indicated by the increasing abundance of n-C-16 acid. This shift likely represents the onset of the current aquatic vegetation structure in the Lake Issyk-Kul. Our findings also highlight the increasing anthropogenic impact on lake ecosystems under relatively stable hydrological conditions. Between 1985 and 2012 CE, the increase in human-induced nutrients fostered the growth of epiphytes. In the 2000s, a sharp rise in microalgal biomass signaled accelerated eutrophication, primarily observed in shoreline areas. These results underscore the critical role of hydrological drivers in shaping the ecological changes in a deep alpine lake over the past similar to 350 years, offering valuable insights into the dynamics of lake ecosystems in arid regions.