<p>Saline lakes are generally characterized by high productivity and accumulation of organic matter, contributing to the global carbon cycle. Mono Lake is an endorheic lake in California (USA) whose geochemistry and microbial community composition have been extensively studied. Less is known about the dissolved organic matter (DOM) composition in this system. Here, we investigated the molecular composition of DOM in Mono Lake using ultrahigh resolution mass spectrometry (FT-ICR MS) to capture patterns of variability in DOM during a transition from monomictic to meromictic conditions in 2017–2018. Dissolved organic carbon (DOC) concentrations were up to twofold higher at ~ 10–15 m in monomictic compared with meromictic conditions. Lake DOM in spring and summer of 2017 was enriched in nitrogen-containing formulae and higher proportions of unsaturated aliphatics, lipid- and protein-like compounds, likely associated with phytoplankton-derived inputs. During fall 2017, lake DOM revealed a more terrestrial signature, and enrichment in sulfur-containing formulae, presumably due to changes in redox condition in the water column. Following prolonged stratification (2018), DOM composition was also influenced by phytoplankton inputs and by the strong redox gradient observed in the lake, with increased relative abundance of S-containing compounds immediately below the pycnocline. During the shift in limnological conditions, Mono Lake DOM remained less aromatic and more reduced than DOM observed in other saline endorheic lakes. These findings shed light on organic carbon cycling in hypersaline lakes, which is important to better constrain contributions of inland aquatic ecosystems to the carbon cycle.</p>