Toxic cyanobacteria are likely to be favored by global warming and other human impacts, posing significant threats to aquatic ecosystems. While cyanobacterial blooms in eutrophic lakes are widely investigated, the dynamics of cyanobacteria and the effects of their toxins and bioactive metabolites on the plankton communities in mesotrophic and oligotrophic lakes are less well understood. Here we investigated seasonal dynamics of cyanobacteria, eukaryotic algae and cyanotoxins in oligo-mesotrophic Lake Geneva—the largest and deepest lake in western Europe. High-throughput sequencing of the 16S rRNA genes in 143 samples along a water column revealed that Lake Geneva hosts diverse, co-dominant cyanobacterial genera, including Planktothrix, Cyanobium, Pseudanabaena, and Aphanizomenon. The abundance of the mcyA gene marker for microcystin production was highly correlated with total cyanobacteria abundance, obtained from qPCR of the 16S rRNA genes. Targeted LC-HRMS/MS analysis demonstrated peak concentrations of cyanotoxins in September and December 2021 at the deep chlorophyll-a maximum layer, reaching up to 1474 ng/l for anabaenopeptins and 144 ng/l for microcystins. The toxin peaks did not correlate with the abundance or variations in the cyanobacteria or eukaryote community, but they were correlated in time with seasonal lows in the abundances of ciliates (18S rRNA analysis). Laboratory exposure tests demonstrated that growth of the model ciliate Tetrahymena pyriformis was inhibited by Microcystin-RR and Anabaenopeptin A at environmentally relevant concentrations in the ng/l-range, in natural lake water, synthetic freshwater, and growth media spiked with the cyanotoxins. Our findings suggest that even low concentrations (in the ng/l-range) of microcystins and anabaenopeptins, reduce growth of ciliates such as T. pyriformis and can be expected to have wider impacts on the eukaryote communities.