Production in many ecosystems is co-limited by multiple elements. While a known suite of drivers associated with nutrient sources, nutrient transport, and internal processing controls concentrations of phosphorus (P) and nitrogen (N) in lakes, much less is known about whether the drivers of single nutrient concentrations can also explain spatial or temporal variation in lake N:P stoichiometry. Predicting stoichiometry might be more complex than predicting concentrations of individual elements because some drivers have similar relationships with N and P, leading to a weak relationship with their ratio. Further, the dominant controls on elemental concentrations likely vary across regions, resulting in context dependent relationships between drivers, lake nutrients and their ratios. Here, we examine whether known drivers of N and P concentrations can explain variation in N:P stoichiometry, and whether explaining variation in stoichiometry differs across regions. We examined drivers of N:P in ~2,700 lakes at a sub-continental scale and two large regions nested within the sub-continental study area that have contrasting ecological context, including differences in the dominant type of land cover (agriculture vs. forest). At the sub-continental scale, lake nutrient concentrations were correlated with nutrient loading and lake internal processing, but stoichiometry was only weakly correlated to drivers of lake nutrients. At the regional scale, drivers that explained variation in nutrients and stoichiometry differed between regions. In the Midwestern U.S. region, dominated by agricultural land use, lake depth and the percentage of row crop agriculture were strong predictors of stoichiometry because only phosphorus was related to lake depth and only nitrogen was related to the percentage of row crop agriculture. In contrast, all drivers were related to N and P in similar ways in the Northeastern U.S. region, leading to weak relationships between drivers and stoichiometry. Our results suggest ecological context mediates controls on lake nutrients and stoichiometry. Predicting stoichiometry was generally more difficult than predicting nutrient concentrations, but human activity may decouple N and P, leading to better prediction of N:P stoichiometry in regions with high anthropogenic activity.