This dataset includes water-quality data for samples collected at sixteen sites in the Clear Lake Drainage Basin, Lake County, California, between November 2018 and March 2024. Sampling in the reach of the Scotts Creek drainage below the confluence with South Fork Scotts Creek (USGS stations 11448800 and 390236122575901) was done during November 2018 to May 2019 (water year 2019; water years (WYs) begin Oct. 1 and end Sept. 30, for example water year 2024 began on Oct. 1, 2023), and also during WYs 2021-24. Sampling at South Fork Scotts Creek near Lakeport (11448750) and Scotts Creek at Eickhoff Road Bridge near Lakeport (390544122574201) was done during WYs 2021-24. Sites on several creeks in the basin were sampled during WYs 2022-24: Clover Creek Bypass at Elk Mountain Road (11449235), Cole Creek at Kelseyville (11449820), Kelsey Creek near Kelseyville (11449500), Kelsey Creek above Soda Bay Road near Kelseyville (390030122502101), and Middle Creek at Rancheria Road (391057122544301). Two sites on Middle Creek were sampled only during WYs 2022-23: Middle Creek Near Vann (391448122565601) and Middle Creek below Elk Mountain Road near Upper Lake (391227122553101). Two sites on Adobe Creek (390054122521501 and 390054122532801) were sampled only during WY 2023. Two sites on Scotts Creek below Tule Lake (11390936122551901 and 11449255) were sampled during WY2021 and WYs 2023-24, respectively, and a site on Molesworth Creek (11449370) was sampled during WYs 2023-24. Sampling events targeted high flows after rain events as well as some lower flow baseline conditions during the wet season (typically December through April) during WYs 2022, 2023, and 2024. Two different sets of analyses (schedules A and B) were assigned to selected sampling sites. Schedule A (116 samples at 6 sites samples during WYs 2022-24), the most complete, included mercury (Hg) species (total Hg (THg) and methylmercury (MeHg), both filtered and particulate), dissolved organic carbon (DOC) and optical properties, filtered and unfiltered nutrients (various forms of nitrogen (N) and phosphorus (P)), and total suspended sediment (TSS). Schedule B (148 samples at 10 sites) consisted of similar analyses as Schedule A but without mercury species, DOC, or optical properties. Stable isotopes of nitrogen and oxygen in dissolved nitrate were analyzed in selected samples from WYs 2022-23. The median and mean grain-size of suspended sediment in selected samples are also reported.