Lewis and students have studied lakes, streams, and wetlands in Colorado and in the American and Southeast Asian tropics. His interests include biogeochemistry of inland waters, food web dynamics, biotic productivity, and environmental factors controlling structure and function of aquatic ecosystems. Examples of recent work include construction and validation of a model that estimates global primary production of lakes under preindustrial conditions and under current conditions, quantification of denitrification rates in flowing waters, and analysis of the effects of anthropogenic nutrients on aquatic ecosystems regionally, nationally, and globally. He is a Lifetime Member Associate of the US National Academy of Sciences and former member of the National Research Council Water Science and Technology Board and Board on Environmental Studies and Toxicology.
Lewis is also recipient of the Renewable Natural Resources Foundation Sustained Achievement Award and of the Naumann Thienemann Medal and the Baldi Award of the International Society for Limnology.