Anthropogenic activity is leading to widespread changes in lake water quality—a key contributor to socio-ecological health. But, the anthropogenic forces affecting lake water quality (climate change, land use change, and invasive species) are unevenly distributed across lakes, across the seasonal cycle, and across space within lakes, potentially leading to highly variable water quality responses that are poorly documented at the global scale. Here, we used 742 million chlorophyll-a (chl-a) estimates merged over 6 satellite sensors (daily, 1 to 4 km resolution) to quantify water quality changes from 1997 to 2020 in 344 globally-distributed large lakes. Chl-a decreased across 56% of the cumulative total lake area, challenging the putative widespread increase in chl-a that is expected due to human activity. 19% of lakes exhibited both positive and negative chl-a trends (p-value < 0.1) across different locations or times of the year. This spatiotemporal complexity demonstrates the value of moderate resolution mapping of lake chl-a to inform water management decision-making and to determine the local ecological consequences of human activity.