Blooms of the toxigenic dinoflagellate Karenia brevis occur regularly in the Gulf of Mexico, especially along the coast of western Florida, U.S.A. Here, time-series data from 1998 to 2020 were used to examine relationships between K. brevis abundance and the El Niño – Southern Oscillation (ENSO) and its rate of change, as well as temperature, precipitation, river flow, and salinity. This time series includes periods of substantial blooms (~ 1.4 × 106 cells L-1) and times characterized by background cell concentrations (~1.0 × 103 cells L-1). El Niño brings wet and cool weather to South Florida, including a greater frequency of storms, while La Niña brings dry and warm weather. However, mild La Niña and periods of ENSO transitions bring a higher frequency of hurricanes that directly impact Florida. Excluding the large bloom of 2020–2021 (not included herein), the highest K. brevis abundances observed were associated with blooms in 2004–2005 and 2017–2018, both of which occurred when hurricanes followed drought periods. High correspondences between cell concentrations, Peace River discharge and ENSO index indicated that freshwater flow, and climate oscillations may play important roles–both direct and indirect–on K. brevis blooms on the West Florida Shelf. These time-series analyses will help to inform new models of bloom formation and termination in western Florida waters and may help to guide nutrient reduction targets from river discharge.