The climate of the southwestern North America has experienced profound changes between wet and dry phases over the past 200 kyr. To better constrain the timing, magnitude and paleoenvironmental impacts of these changes in hydroclimate, we conducted a multiproxy biomarker study from samples collected from a new 76 m sediment core (SLAPP-SRLS17) drilled in Searles Lake, California. Here, we use biomarkers and pollen to reconstruct vegetation, lake conditions and climate. We find that δD values of long chain n-alkanes are dominated by glacial to interglacial changes that match nearby Devils Hole calcite δ18O variability, suggesting both archives predominantly reflect precipitation isotopes. However, precipitation isotopes do not simply covary with evidence for wet-dry changes in vegetation and lake conditions, indicating a partial disconnect between large scale atmospheric circulation tracked by precipitation isotopes and landscape moisture availability. Increased crenarchaeol production and decreased evidence for methane cycling reveal a 10 kyr interval of a fresh, productive and well-mixed lake during Termination II, corroborating evidence for a paleolake highstand from shorelines and spillover deposits in downstream Panamint Basin during the end of the penultimate (Tahoe) glacial (140–130 ka). At the same time brGDGTs yield the lowest temperature estimates (mean months above freezing = 9 ± 3°C) of the 200 kyr record. These limnological conditions are not replicated elsewhere in the 200 kyr record, suggesting that the Heinrich stadial 11 highstand was wetter than that during the last glacial maximum and Heinrich 1 (18–15 ka).