Land use and climate change are anticipated to affect phytoplankton of lakes worldwide. The effects will depend on the magnitude of projected land use and climate changes and lake sensitivity to these factors. We used random forests fit with long-term (1971–2016) phytoplankton and cyanobacteria abundance time series, climate observations (1971–2016), and upstream catchment land use (global Clumondo models for the year 2000) data from 14 European and 15 North American lakes basins. We projected future phytoplankton and cyanobacteria abundance in the 29 focal lake basins and 1567 lakes across focal regions based on three land use (sustainability, middle of the road, and regional rivalry) and two climate (RCP 2.6 and 8.5) scenarios to mid-21st century. On average, lakes are expected to have higher phytoplankton and cyanobacteria due to increases in both urban land use and temperature, and decreases in forest habitat. However, the relative importance of land use and climate effects varied substantially among regions and lakes. Accounting for land use and climate changes in a combined way based on extensive data allowed us to identify urbanization as the major driver of phytoplankton development in lakes located in urban areas, and climate as major driver in lakes located in remote areas where past and future land use changes were minimal. For approximately one-third of the studied lakes, both drivers were relatively important. The results of this large scale study suggest the best approaches for mitigating the effects of human activity on lake phytoplankton and cyanobacteria will depend strongly on lake sensitivity to long-term change and the magnitude of projected land use and climate changes at a given location. Our quantitative analyses suggest local management measures should focus on retaining nutrients in urban landscapes to prevent nutrient pollution from exacerbating ongoing changes to lake ecosystems from climate change.