Witherell has done particle physics research at accelerators and underground. His current research is part of the campaign to observe the interactions of dark matter particles with ordinary matter. He is working on the LUX (Large Underground Xenon) experiment, which is now operating in the Sanford Underground Research Facility (SURF) in the Black Hills of South Dakota. He is a member of the LUX-ZEPLIN (LZ) collaboration, which is building a much more sensitive experiment to start operating at SURF in 2019.
He is interested in pursuing the search for neutrinoless double beta decay using LZ, in addition to the dark matter search for which it was principally designed.