Seung has done influential research in both computer science and neuroscience. Over the past decade, he helped pioneer the new field of connectomics, developing machine learning and social computing technologies for reconstructing neural circuits from high resolution brain images. His lab created EyeWire, a site that has recruited over 150,000 players from 130 countries to a game to map neural connections.

Seung is also known for his efforts to communicate neuroscience to the general public. His TED Talk "I am my connectome" has more than 750,000 views, and has been translated into 26 languages. His book Connectome: How the Brain's Wiring Makes Us Who We Are was chosen by the Wall Street Journal as Top Ten Nonfiction of 2012.

He is an External Member of the Max Planck Society, and winner of the 2008 Ho-Am Prize in Engineering.