Northern Eurasia underwent major hydroclimatic changes since the beginning of the Holocene interglacial. A rapid warming period reaching the Holocene Thermal Maximum (HTM), followed by a general cooling trend until recent times, was observed in Eurasian lacustrine diatom oxygen isotope (δ18Odiatom) records. In this study, we present a new Holocene δ18Odiatom record from Lake Khamra (59.99°N, 112.98°E, Siberia). Our record aligns with Holocene δ18Odiatom records across the Northern Hemisphere, showing a general millennial-scale cooling trend following an initial maximum at 11.2 cal. ka BP and a second maximum at 6.7 cal. ka BP. These maxima correspond to the summer insolation maximum and elevated Northern Hemisphere air temperatures, as well as increased bioproductivity. Variability on centennial scales is likely driven by precipitation changes, which coincide with higher sedimentation rates and overlay the general decreasing trend throughout the Holocene. In addition, we compared two multiproxy datasets with decadal resolution from Lake Khamra, including δ18Odiatom data and biogeochemical proxies such as total organic carbon (TOC), total nitrogen (TN), stable carbon (δ13C) and nitrogen (δ15N) isotopes, and total mercury (THg). The datasets cover a ~210-year period (c. 6.140–6.350 cal. ka BP) at the end of the HTM and a recently published ~220-year record (c. 1790–2015 CE) that embraces the anthropogenic times. The comparison of these two warm phases reveals distinct differences in both the absolute values and the variability of the records. Regarding the δ18Odiatom data, the recent period shows a nearly threefold increase in range and double the standard deviation, suggesting greater hydroclimatic variability compared to the end of the HTM. Notably, THg levels indicate a sharp increase in recent decades, while δ13C declined, contrasting with the observations at the end of the HTM. We attribute these observations partially to far-reaching anthropogenic effects on remote lake systems.