Karletta Chief's research interests include environmental processes in arid soils and the effects of climate change on water resources and Indigenous people. As an extension specialist, Chief works to translate university research for Native Americans in Arizona and has done so in a range of areas, including watershed hydrology, mining impacts, water policy, culturally relevant food safety, and climate change assessment and adaptation.

Chief, who is Diné, is also director of the university's Indigenous Resilience Center. Launched in 2021, the Center develops projects and partnerships with Native Nations to advance tribal communities' efforts to respond to environmental challenges and become more resilient. Chief is also chair of the Graduate Interdisciplinary Program (GIPD) PhD Minor in Indigenous food, energy and water systems. She supervises and advises the research of students working on topics related to tribal environmental issues.

In 2016, Chief was named the American Indian Science and Engineering Society's Professional of the Year; the organization named her Most Promising Engineer or Scientist 2010. In 2017, Stanford University's Native American Cultural Center named Chief to the university's Multicultural Alumni Hall of Fame. She also was awarded the Phoenix Indian Center's 2016 Outstanding Woman of the Year and the American Geophysical Union's 2020 Ambassador Award, and she was named among the National Center for American Enterprise Development's 2015 Native American 40 Under 40.